Programs

Cellular Plasticity & Cancer Group

María Abad
Principal Investigator
Biosketch
Principal Investigator Maria Abad Post-Doctoral Fellow Elena Senis Graduate Students Olga Boix, Alba Escriche, Emanuela Greco, Marion Martinez, Iñaki Merino Research Assistant Mireia Jimenez Technician Marta Gimenez

Summary

Our group focuses on the interplay between cellular plasticity, stem cells and cancer. Cellular plasticity is recognized today as a critical feature of cancer cells that enables them to transit between different cellular states, including reversible transitions between mesenchymal and epithelial phenotypes, or stem cell-like and differentiated states. In tumors, the acquisition of stem cell properties correlates with increased malignancy and poor prognosis, and Cancer Stem Cells (CSCs) sustain the tumor bulk and contribute to treatment resistance and disease relapse post-therapy.

In this respect, we have reported that inducing dedifferentiation with the so-called Yamanaka factors can lead to the development of a variety of tumors. We have also demonstrated that tissue damage, as the main driver of cancer, triggers cell dedifferentiation and the acquisition of stem cell properties in vivo.

These observations have important therapeutic implications given that chemotherapy and radiotherapy – cornerstones for the treatment of most cancers – could have the side effect of inducing stemness in non-stem cancer cells and, in turn, possibly contribute to tumor recurrence and metastasis.

Our main objective is to better understand the mechanisms and players implicated in this process, with the ultimate goal of developing novel therapies based on the inhibition of cancer cell plasticity.

Recent findings have demonstrated that some genomic regions, previously considered as non-coding (including lncRNAs), contain small open reading frames encoding for evolutionary conserved, unannotated micropeptides. The few that have been identified to-date play key functions in elemental cellular processes, leading to a new level of complexity with major implications – from basic research to the clinical setting.

Over the past three years we have focused on identifying and characterizing novel cancer micropeptides that could represent novel actors in carcinogenesis.We have discovered six new cancer micropeptides and have obtained compelling evidence in vitro and in vivo that four of them act as novel tumor suppressors, inducing cell cycle arrest, differentiation or inhibition of mesenchymal traits in cancer cells.

The identification of tumor-micropeptides could be crucial in advancing insights into cancer physiopathology. Moreover, they could also serve as new cancer biomarkers for the early detection of disease and patient stratification for tailored therapies, as well as therapeutic targets.

In 2019, we have expanded our micropeptides studies and embarked on a new project that aims to identify novel secreted micropeptides that act as crucial cellular messengers for pancreatic cancer metastasis.


< 100 aa
Evolutionary conserved
Very few functionally characterized
Key roles in essential cellular functions
We have identified 6 cancer micropeptides

Strategic goals

  • Discover and characterize novel micropeptides involved in cancer cell plasticity.
  • Generate new patient-stratification tools based on cancer micropeptides.
  • Develop new therapeutic-agents based on novel micropeptides.
  • Decipher the molecular mechanisms governing the acquisition of stem cell properties during tumorigenesis.
  • Develop new anti-cancer therapies based on the inhibition of cancer cell plasticity.

Highlights

  • We were awarded with the Health Research Grant 2018 from the ”la Caixa” Foundation.
  • We also received the Health Research Grant from La Mutua Madrileña Foundation.
  • María Abad was invited as a guest editor for the first ever special issue on small-ORF encoded microproteins published in Experimental Cell Research.
  • María Abad co-devised and launched the VHIO–”la Caixa” Scientific Seminars Series as Scientific Co-Chair alongside Laura Soucek (PI, Mouse Models of Cancer Therapies Group), and Elena Élez (Medical Oncologist and Clinical Investigator, Gastrointestinal & Endocrine Tumors Group).

Horizons

  • Develop cell-penetrating micropeptides as new therapeutic targets.
  • Identify micropeptides in cancer patients-plasma by proteogenomics.
  • Discover micropeptides secreted in exosomes by tumor cells.
  • Study the role of cellular dedifferentiation in breast and pancreatic cancer.
  • Investigate the tumor-stroma crosstalk after chemo/radiotherapy in PDAC and its impact on tumor cell plasticity.

Awards and Recognition

  • We were awarded with the Health Research Grant 2018 from the La Caixa Foundation.
  • We also received the Health Research Grant from La Mutua Madrileña Foundation.

Projects

  1. Defining the Role of Exosome-Secreted Micropeptides in Pancreatic Cancer. number: HR18-00256.Health Research Grant-La Caixa Foundation.
    Award Period: 9/2019-8/2021.
    PI: Maria Abad.
  2. Identificación y Análisis del Microproteoma del Cáncer de Páncreas: Los Micropéptidos como Nuevas Dianas Terapéuticas y Biomarcadores Tumorales Fundación. XVI Convocatoria de Ayudas a la Investigación en Salud. Fundación Mutua Madrileña.
    01/09/2019-30/08/2022.
    PI: Maria Abad.
  3. Mining the Microproteome for New Molecular Targets in Cancer. number: RTI2018-102046-B-I00.Spanish Ministry of Economy and Competitiveness.
    1/2019-12/2021.
    PI: Maria Abad.
  4. Cellular Plasticity in Tissue Regeneration and Cancer. Ref. number: RYC-2013-14747.
    Spanish Ministry of Economy and Competitiveness.
    Award Period: 9/2015-8/2020.
    PI: Maria Abad.

Chromatin Dynamics in Cancer Group

Sandra Peiró
Principal Investigator
Biosketch
Principal Investigator Sandra Peiró Post-Doctoral Fellows Laura Pascual, Gemma Serra Graduate Students Marc Cosin, Carmen Escudero, Queralt Serra Students Josep Francesch, Laura Mondejar, Macarena Palacios Technician Jessica Querol

Summary

Our laboratory seeks to better understand how epigenetics and chromatin structure and dynamics affect cell behavior, with a specific focus on cancer. Through our comprehensive studies, we aim to dissect the role of epigenetic changes in cancer, identify mechanisms of response and resistance to anti-cancer medicines, and explore new therapeutic opportunities.

Over the last few years, we have elucidated epigenetic changes during EMT and cancer progression, and discovered a new histone H3 modification (oxidized H3) enriched in heterochromatin that is implicated in chromatin condensation and the transition to a metastatic cell fate (published in Mol. Cell, FEBS J., and Oncogene). We have also discovered an important role for lamin B1 in the reorganization of 3D chromatin structure during EMT (published 2018, Nat. Commun.).

Dedicated to fully applying these insights to the epigenetic landscape and 3D structure during this malignant transformation, we have adopted chromosome conformation–based techniques together with ChIP-seq, ATAC-seq and RNA-seq. By combining these data with excellent computational and statistical tools in standard cancer models, such as cancer cell lines, and in a large and unique collection of patient-derived xenograft (PDX) models, we will continue to navigate this largely uncharted area which shows great promise in the early diagnosis of disease.

We are equally committed to describing the association of chromatin conformation modifications with the acquisition of malignant traits and evaluating the functional consequences of these developments in genes and pathways. Next steps will involve deciphering how these alterations occur at the molecular level and more precisely identifying these putative culprits for future targeted therapy


Triple negative breast cancer cells.

Strategic goals

The laboratory has two main goals:
  • To understand the 3D chromatin structure and dynamics in cancer from a basic research perspective.
  • Identify biomarkers and epigenetic mechanisms of drug response and resistance in ER+ breast cancer, cholangiocarcinomas, and NUT-midline carcinomas.
Specifically:
  • Which molecular events direct chromatin movements?
  • Are these events due to the specific binding of a subset of transcription factors?
  • To what extent are chromatin architecture changes reversible?
  • During the process of metastasis cells go through an intermediate state. Does this state possess a specific and genomic architecture that determines the metastatic fate? Could we block this ?
  • What is the role of oxidized H3 in other tumor types? Could we inhibit this oxidation using a peptide-based therapy?
  • Identification of key epigenetic components using PDXs, Cas9–cholangiocarinoma cell lines, and organoids with epigenetic drugs currently used in clinical trials.
  • Can we combine different drugs to overcome resistance?
  • Which are the biomarkers that will enable us to stratify patients for more effective treatments?

Highlights

  • We have discovered the molecular function of oxidize Histone H3 in TNBC.
  • We have consolidated our collaboration with VHIO’s Gastrointestinal & Endocrine Tumors Group (PI: Teresa Macarulla) through a grant received from La Marató TV3 Foundation.
  • Gemma Serra obtained her PhD from the Pompeu Fabra University, Barcelona, with magna cum laude.

Horizons

Our main goals are to:
  • Understand the 3D chromatin structure and dynamics in cancer;
  • Identify biomarkers and epigenetic mechanisms of drug response and resistance in ER+ breast cancer (BC), CCAs, and NMCs;
  • Explore new therapeutic opportunities.

PI paper pick

  • Cebrià-Costa JP, Pascual-Reguant L, Gonzalez-Perez A, Serra-Bardenys G, Querol J, Cosín M, Verde G, Cigliano RA, Sanseverino W, Segura-Bayona S, Iturbide A, Andreu D, Nuciforo P, Bernado-Morales C, Rodilla V, Arribas J, Yelamos J, de Herreros AG, Stracker TH, Peiró S. LOXL2-mediated H3K4 oxidation reduced chromatin accessibility in triple negative breast cancer cells. Oncogene. 2020 Jan;39(1):79-121. Epub 2019 Aug 28.

Projects

  1. Identificación y caracterización de nuevos elementos reguladores durante la adquisición de competencias metastásicas en un modelo de transición epitelio-mesénquima y en tumores de mama triple-negativos.
    Spanish Carlos III Health Institute (FIS)
    2019–2022
  2. .
  3. Epigenetic Landscape Characterization of Cholangiocarcinomas.
    Fundació Marató TV3
    2020–2023
  4. .

Experimental Therapeutics Group

Violeta Serra
Principal Investigator
Biosketch
Principal Investigator Violeta Serra Post-Doctoral Fellows Alba Llop-Guevara, Marta Palafox, Mónica Sánchez Graduate Students Marta Castroviejo, Laia Monserrat, Flaminia Pedretti Visiting Students Alais Marie Berthod, Andreu Odena, María Jimena Rodríguez Technicians Judit Grueso, Marta Guzmán, Andrea Herencia, Mireia Pares, Olga Rodríguez

Summary

VHIO’s Experimental Therapeutics Group conducts bench-to-bedside preclinical research in breast cancer to advance insights into biomarkers of response to targeted therapies. To do so, we generate preclinical models such as patient-derived xenografts (PDXs) and patient-derived cultures (PDCs) from breast cancer patient samples.

Our group has significantly contributed to the field of PI3K inhibitor resistance and we continue to explore mechanisms of resistance to CDK4/6 inhibitors, FGFR inhibitors, AKT inhibitors and AR modulators (SARMs) in breast tumors in greater depth.

Using clinically relevant PDXs we provided data to further support that loss of G1-cell cycle checkpoint control, such as mutation/loss of RB1 or CCND1-amplification, is associated with lack of response to CDK4/6 blockade in estrogen receptor positive breast cancer. We have also generated a collection of PDXs containing FGFR amplification to study biomarkers of sensitivity to FGFR inhibitors; both pan-FGFR1-4 and Multi-targeted Tyrosine Kinase Inhibitors (MTKIs).

Encouraged by the early success of DNA damage repair inhibitors in germline BRCA1/2 mutated tumors, we initiated a project aimed at identifying response biomarkers of PARP inhibitors (PARPi) as well as other DNA damage repair inhibitors including those targeting WEE1 or ATR.

Our studies underpin the capacity of germline BRCA mutant tumors to recover HRR functionality and develop resistance to PARPi. We have developed an assay, the RAD51predict test, which accurately identifies germline BRCA tumors that have restored HRR functionality and become resistant to these drugs. Importantly, this test also identifies tumors that are sensitive to PARPi through HRR alterations beyond the germline BRCA condition. We filed a patent (EU application in 2017 and PCT in 2018), and we are currently validating the use of this test in tumor samples from breast, ovarian and prostate cancer patients.

Finally, we are also studying the effects of PARPi on the tumor immune environment. HRR-deficient tumors have been shown to accumulate cytosolic DNA, which can elicit an innate immune signal (the STING pathway) and upregulate interferon-related genes, leading to lymphocytic infiltration and PD-L1 expression. We are testing the hypothesis that treatment of HRR-deficient tumors with PARPi elicits a DNA damage response that results in upregulation of PD-L1 and might limit the antitumor immune-mediated cytotoxicity by lymphocytes, but sensitizes to anti-PD-L1 treatments.

In short, working closely together with Cristina Saura’s Breast Cancer Group, and Judith Balmaña’s Hereditary Cancer Genetics Group, our team has significantly advanced the understanding of the mode of action of novel targeted therapies, identified new response biomarkers and developed a biomarker-based assay with potential clinical application. We have also demonstrated the efficacy of hypothesis-based drug combinations.

Reflective of VHIO’s purely multidisciplinary and translational approach, our research is also carried out through collaborations with other groups including VHIO’s Molecular Oncology, and Oncology Data Science – OdysSey Groups directed by Paolo Nuciforo and Rodrigo Dienstmann, respectively.


RAD51predict (predictor of PARPi response) is an immune-based assay, performed on FFPE tumor sections, that identifies nuclear biomarkers and determines the functionality of the HRR DNA-damage pathway and the response to PARPi therapy. It has been validated in PDX models and we are currently extending the clinical validation to several tumor types.
Generation of patient-derived culture cells (PDCs) coming from BC PDXs: after mechanical and enzymatic disaggregation, cells are seeded in suspension or matrigel cultures for pharmacodynamic analysis and for drug efficacy assay (spheroid area and EdU incorporation). Representative images and data of each approach are shown.

Strategic goals

  • Developing predictive biomarkers of targeted treatments in ER+ and TN breast cancers, including inhibitors directed against the DNA damage repair protein PARP and against signaling/cell cycle kinases (CDK4/6, PI3K/AKT or FGFR).
  • Exploring novel treatment combinations for ER+ and TN breast cancers.
  • Contributing to personalized medicine by developing a diagnostic test to better guide treatment strategies based on PARP inhibitors.
  • Establishing patient tumor-derived breast cancer preclinical models to explore hypothesis-based combinatorial therapies.

Highlights

  • We have contributed towards a better understanding of the mechanisms underlying BRCA1 restoration that confer resistance to PARP inhibitors.
  • We described that the natural inhibitor of CDK4/6, p16, alters target engagement of CDK4/6 inhibitors, implying that high levels of p16 may impede drug binding.
  • We have obtained funding from the ERA PerMed as well as the CaixaImpulse programs to clinically validate and further implement a diagnostic test to identify PARP inhibitor sensitive tumors.
  • Our group has established a panel of over one hundred ER+ and TN breast cancer PDXs, mainly from the metastatic disease setting. We especially focus on models that recapitulate the progression to CDK4/6 inhibitors and BRCA1/2-associated tumors.

Horizons

  • Identification of response and resistance biomarkers to PI3K/AKT, FGFR,CDK4/6 inhibitors and AR modulators in breast cancer and validation in pre-clinical and clinical cohorts. Based on these results, new patient stratification and therapeutic algorithms will be proposed for improving the response of patients who do not show clinical benefit from current therapies.
  • Unveil genetic and epigenetic mechanisms of acquired resistance to PARP inhibitors in hereditary BRCA1/2 breast cancer and beyond; by means of other HRR alterations in other diseases such as prostate cancer.
  • Optimization of the RAD51 assay to be used in liquid biopsies (CTCs in blood) and automatization of the staining and image analysis of the test to ease its future implementation in the clinics.
  • Extensive clinical validation of the RAD51 assay in different tumor types as a biomarker of HRR functionality, PARPi response and clinical outcome (disease prognosis).
  • Dissect the role of the STING pathway in BRCA mutated tumors and explore the combination of PARPi and anti-PD-L1 therapies.
  • Continue expanding the panel of patient tumor-derived breast cancer models to investigate hypothesis-based, clinically-applicable therapy combinations in breast cancer aimed at overcoming resistance to both anti-oestrogen therapy and PARP inhibitors.

PI paper pick

  • Pellegrino B, Mateo J, Serra V, Balmaña J. Controversies in oncology: are genomic tests quantifying homologous recombination repair deficiency (HRD) useful for treatment decision making? ESMO Open. 2019 May 9;4(2):e000480.
  • Mateo J, Lord CJ, Serra V, Tutt A, Balmaña J, Castroviejo-Bermejo M, Cruz C, Oaknin A, Kaye SB, de Bono JS. A decade of clinical development of PARP inhibitors in perspective. Ann. Oncol. 2019 Sep 1;30(9):1437-1447.
  • Gourley C, Balmaña J, Ledermann JA, Serra V, Dent R, Loibl S, Pujade-Lauraine E, Boulton SJ. Moving From Poly (ADP-Ribose) Polymerase Inhibition to Targeting DNA Repair and DNA Damage Response in Cancer Therapy. J. Clin. Oncol. 2019 Sep 1;37(25):2257-2269.
  • Green JL, Okerberg ES, Sejd J, Palafox M, Monserrat L, Alemayehu S, Wu J, Sykes M, Aban A, Serra V, Nomanbhoy T. Direct CDKN2 Modulation of CDK4 Alters Target Engagement of CDK4 Inhibitor Drugs. Mol. Cancer Ther. 2019 Apr;18(4):771-779.

Awards and Recognition

  • Our Principal Investigator, Violeta Serra – along with Judith Balmaña, PI of VHIO’s Hereditary Cancer Genetics Group- received  the very first joint FERO-GHD Award in 2019. This funding will spur research into developing liquid biopsy to monitor response to therapy and establish the sensitivity of breast cancer patients with BRCA1/2 mutations to treatment with PARP inhibitors. The goal is to more effectively tailor personalized treatment regimens to the unique specificities of each particular cancer, more effectively tackle cancer drug resistance, as well as establish which patients would be most likely to benefit from these targeted therapies.
  • Violeta Serra received La Marató funding to investigate mechanisms of resistance to therapy with PARP inhibitors (PARPi). By liquid biopsy, Violeta’s team will aim to establish whether the RAD51 biomarker, that can predict sensitivity to PARPi, can more effectively identify the patients who will be most likely to benefit.

Projects

New projects awarded in 2019, commencing in 2020:
  1. RAD51predict: Patient stratification based on DNA repair functionality for cancer precision medicine(ERAPERMED2019-215).
    Funding Agency: ERA Net
    Coordinator: Violeta Serra
    Duration: 2020-2022
  2. Liquid biopsies for the identification of mechanisms of resistance to PARP inhibitors in BRCA1/2-associated cancers (654/C/2019).
    Funding Agency: La Marató TV3
    Coordinator: Violeta Serra
    Duration: 2020-2022
Projects awarded/initiated in 2019:
  1. Development of a liquid biopsy test to assess the homologous recombination function status in BRCA1/2 mutation carriers with breast cancer to inform therapy selection.
    Funding Agency: FERO Foundation
    Principal Investigator: Violeta Serra
    Duration: 2019-2020
  2. Modulation of androgen receptor signalling as a therapeutic strategy for oestrogen receptor-positive metastatic breast cancer(2018NovPCC1291).
    Funding Agency: Breast Cancer Now
    Principal Investigator: Violeta Serra
    Duration: 2019-2021
Other ongoing projects:
  1. Targeted agents against PARP, WEE1, ATR and ATM in TNBC: mechanisms of action, biomarkers of sensitivity and immunomodulation (PI17/01080).
    Funding Agency: ISCIII
    Principal Investigator: Violeta Serra
    Duration: 2018-2020
  2. New predictive factors of response to targeted therapies and prognostic factors in breast cancer with germline mutations in BRCA1 and BRCA2: DNA damage repair capacity and tumor immunological profile (LABAE16020PORT).
    Funding Agency: AECC (Spanish Association Against Cancer)
    Principal Investigator: Violeta Serra
    Duration: 2018-2020

Gene Expression & Cancer Group

Joan Seoane
Principal Investigator
Biosketch
Principal Investigator Joan Seoane Post-Doctoral Fellows Ester Bonfill, Laura Escudero, Raffaella Iurlaro, Monica Pascual, Ester Planas, Carlota Rubio, Research Fellow, Davide Ciardiello Masters Student Samia Hajem Graduate Student Ester Arroba Technicians Alexandra Arias, Mª Isabel Cuartas, Alba Martinez

Summary

We study primary brain tumors and brain metastasis; some of the most aggressive of all cancers. Both glioblastoma and brain metastasis are dismal diseases with limited therapeutic options. Advancing progress in this field towards improving outcomes for these patients is therefore critical.

Evolving heterogeneity is among one of the major challenges that are currently hampering our efforts aimed at more effectively treating brain cancers. We focus on inter-tumor heterogeneity and evolution that includes genomic heterogeneity, cancer initiating cells and stroma/immune cell heterogeneity – including the study of TGF-β and LIF.

Tumors are composed of a mosaic of cell subclones that differ in their genomic alterations. Our group explores the genomic diversity present in glioblastoma and analyzes intratumor genomic heterogeneity as it evolves over time in response to therapy. We are designing tools to monitor evolving genomic heterogeneity, and studying the use of liquid biopsies for brain cancer through the study of circulating cell free tumor DNA in cerebrospinal fluid from patients.

Specifically, we are driving cerebrospinal fluid as liquid biopsy for the real time policing of brain cancer closer to the clinic. Reflective of our expertise in developing this novel approach, we recently first-authored an article (Seoane et al. Ann Oncol. 2019), analyzing several studies on the use of liquid biopsy in primary and metastatic brain tumors for the diagnosis and follow-up of disease as well as the detection of mechanisms of resistance or susceptible mutations.

While no biomarker derived from liquid biopsy against these tumor types has yet been validated and integrated into clinical practice, there is an increasing body of evidence in the literature, including our findings, that points to its efficacy in the real time evaluation of malignant disease and potential in better guiding the therapeutic management of patients.

We are as equally committed to furthering insights into the role of the tumor microenvironment which, in the case of brain cancers, assumes a crucial role in cancer progression. Advancing discovery into the tumor microenvironment promises a way of combating cancer independently of its heterogeneity.

By eliminating the niche where tumors reside and thrive should help us to develop more effective anti-cancer compounds. In this context, we have reported that the cytokine LIF assumes an essential role in the tumor microenvironment and is consequently a promising therapeutic target.

Building on our previous LIF studies, where we were the first to establish a link between this multi-functional protein and cancer, as well as show that LIF blockade eliminates cancer stem cells and prevents disease progression and recurrence, subsequent research has led to the publication of a further article this year directed by our Group (Pascual-García et al. Nat Commun. 2019.)

We have now shown that the novel agent MSC-1, developed by VHIO, inhibits LIF and has now been shown to have a dual mechanism of action. In tumors expressing high levels of LIF, this protein promotes the proliferation of cancer stem cells. LIF blockade eliminates these tumor-initiating stem cells, putting the brakes on metastatic cell spread and cancer recurrence.

Additionally, elevated LIF expression disables the anti-tumor alarm system and stops the immune system from thwarting cancer’s plans. Blocking LIF reactivates the alarm to call an anti-tumoral immune response.


Novel agent MSC-1 reactivates an immune call by LIF blockade.

Strategic goals

  • Identify new therapeutic targets against brain tumors and novel biomarkers to more precisely predict response to therapy.
  • Study intratumor heterogeneity.
  • Investigate the tumor microenvironment.
  • Develop methods for non-invasive molecular diagnosis through the study of circulating biomarkers.
  • Generate patient-derived mouse models of brain cancers.

Highlights

  • We have successfully translated our discoveries into a clinical trial. Having initiated a first-in-human and first-in-class clinical trial last year with a novel compound, MSC-1 – designed by our group and developed by the VHIO born spin-off, Mosaic Biomedicals, that Joan Seoane founded in 2012 - we have now completed the Phase I study.
  • We continue to develop liquid biopsies based on the analysis of cell free circulating tumor DNA in cerebrospinal fluid for the diagnosis, prognosis and monitoring of patients with brain tumors.
  • Building on our previous research showing the superiority of CSF over plasma, we have embarked on a joint project funded by the Spanish Association against Cancer (AECC). In partnership with colleagues at the Hospital 12 de Octubre (Madrid), and Hospital Clinic de Barcelona, we will develop this concept and determine how it could be implemented in clinical practice.
  • Joan Seoane was awarded by the Ramón Areces Foundation in 2019 to seek out novel immunotherapeutic targets in brain metastases. In multidisciplinary collaboration with Enriqueta Felip, PI of VHIO’s Thoracic Tumors & Head and Neck Cancer Group, and Eva Muñoz, Clinical Investigator of our Breast Cancer & Melanoma Group (PI: Cristina Saura), he will analyze patients’ brain metastases and compare them with respective primary tumors to reveal factors governing clinical response to immune checkpoint blockade

Horizons

Our main goals are to:
  • Identify novel therapeutic targets against brain tumors.
  • Advance insights into the brain tumor microenvironment.
  • Develop and translate methods for the non-invasive characterization of brain tumors (liquid biopsy) into clinical practice.

PI paper pick

  • Pascual-García M, Bonfill-Teixidor E, Planas-Rigol E, Rubio-Perez C, Iurlaro R, Arias A, Cuartas I, Sala-Hojman A, Escudero E, Martínez-Ricarte F, Huber-Ruano I, Nuciforo P, Pedrosa L, Marques C, Braña I, Garralda E, Vieito M, Squatrito M, Pineda E, Graus F, Espejo C, Sahuquillo J, Tabernero J, Seoane J. LIF regulates CXCL9 in tumor-associated macrophages and prevents CD8 + T cell tumor-infiltration impairing anti-PD1 therapy. Nat Commun. 2019 Jun 11;10(1):2416.
  • Seoane J, De Mattos-Arruda L, Le Rhun E, Bardelli A, Weller M. Cerebrospinal fluid cell-free tumour DNA as a liquid biopsy for primary brain tumours and central nervous system metastases. Ann Oncol. 2019 Feb 1;30(2):211-218.
  • Siravegna G, Mussolin B, Venesio T, Marsoni S, Seoane J, Dive C, Papadopoulos N, Kopetz S, Corcoran RB, Siu LL, Bardelli A. How liquid biopsies can change clinical practice in oncology. Ann Oncol. 2019 Oct 1;30(10):1580-1590.
  • De Mattos-Arruda L, Sammut SJ, Ross EM, Bashford-Rogers R, Greenstein E, Markus H, Morganella S, Teng Y, Maruvka Y, Pereira B, Rueda OM, Chin SF, Contente-Cuomo T, Mayor R, Arias A, Ali HR, Cope W, Tiezzi D, Dariush A, Dias Amarante T, Reshef D, Ciriaco N, Martinez-Saez E, Peg V, Ramon Y Cajal S, Cortes J, Vassiliou G, Getz G, Nik-Zainal S, Murtaza M, Friedman N, Markowetz F, Seoane J, Caldas C. The Genomic and Immune Landscapes of Lethal Metastatic Breast Cancer. Cell Rep. 2019 May 28;27(9):2690-2708.

Awards and Recognition

  • Joan Seoane was awarded by the Ramón Areces Foundation in 2019 to seek out novel immunotherapeutic targets in brain metastases.

    In multidisciplinary collaboration with Enriqueta Felip, PI of VHIO’s Thoracic Tumors & Head and Neck Cancer Group, and Eva Muñoz, Clinical Investigator of our Breast Cancer & Melanoma Group (PI: Cristina Saura), he will analyze patients’ brain metastases and compare them with respective primary tumors to reveal factors governing clinical response to immune checkpoint blockade.

Projects

  1. Grantor: Fundación Científica de la AECC
    Title:  Study of the molecular mechanisms involved in primary (glioblastoma) and secondary (metastasis) brain tumors to identify novel therapeutic targets and anti-cancer agents, biomarkers to select treatments and novel non-invasive methods for molecular diagnosis.

    Project Reference: GCTRA16015SEDA
    Role in the Project: Principal Investigator
    2017-2022.
  2. Grantor: IBEC-La Caixa
    Title: Understanding and measuring mechanical tumor properties to improve cancer diagnosis, treatment, and survival: Application to liquid biopsies
    Project Reference:
    Role in the Project: Principal Investigator
    2017-2020.
  3. Grantor: Institute of Health Carlos III – FIS (Ministry of Science and Innovation-MICINN) Title:Identificación de mecanismos de resistencia a tratamiento a través del estudio de la heterogeneidad intra-tumoral en glioblastoma
    Project Reference: Ref. PI16/01278
    Role in the project: Principal Investigator
    2017-2019.
  4. Institute of Health Carlos III – Sara Borrell
    Title: Papel de LIF y TDFb en la regulación del sistema inmunológico en glioblastoma y metástasis cerebrales
    Project Reference: CD18/00223
    Role in the project: Principal Investigator
    2019-2021.
  5. Ramon Areces Foundation.
    Title: Identification of novel immunotherapeutic targets in lung and melanoma brain metastases.
    Project reference: CIVP19A5943
    Role in the Project: Principal Investigator
    2019-2022.
  6. FERO
    Title: Caracterización molecular mediante el estudio del ADN circulante en líquido cefalorraquídeo para la mejora del tratamiento del tumor cerebral pediátrico, meduloblastoma
    2019-2020.

Full list of Publications

  • Pascual-GarcíaM, Bonfill-TeixidorE, Planas-RigolE, Rubio-PerezC, IurlaroR,AriasA, Cuartas I, Sala-HojmanA, Escudero E, Martínez-Ricarte F, Huber-Ruano I, NuciforoP, PedrosaL, MarquesC, BrañaI, GarraldaE, VieitoM, SquatritoM, PinedaE, GrausF, EspejoC, SahuquilloJ, TaberneroJ, SeoaneJ. LIF regulates CXCL9 in tumor-associated macrophages and prevents CD8+T cell tumor-infiltration impairing anti-PD1 therapy. Nat Commun. 2019 Jun 11;10(1):2416.
  • SeoaneJ, De Mattos-ArrudaL, Le RhunE, BardelliA, WellerM. Cerebrospinal fluid cell-free tumour DNA as a liquid biopsy for primary brain tumours and central nervous system metastases. Ann Oncol. 2019 Feb 1;30(2):211-218.
  • Siravegna G, Mussolin B, Venesio T, Marsoni S, Seoane J, Dive C, Papadopoulos N, Kopetz S, Corcoran RB, Siu LL, Bardelli A. How liquid biopsies can change clinical practice in oncology. Ann Oncol. 2019 Oct 1;30(10):1580-1590.
  • De Mattos-Arruda L, Sammut SJ, Ross EM, Bashford-Rogers R, Greenstein E, Markus H, Morganella S, Teng Y, Maruvka Y, Pereira B, Rueda OM, Chin SF, Contente-Cuomo T, Mayor R, Arias A, Ali HR, Cope W, Tiezzi D, Dariush A, Dias Amarante T, Reshef D, Ciriaco N, Martinez-Saez E, Peg V, Ramon Y Cajal S, Cortes J, Vassiliou G, Getz G, Nik-Zainal S, Murtaza M, Friedman N, Markowetz F, Seoane J, Caldas C.The Genomic and Immune Landscapes of Lethal Metastatic Breast Cancer. Cell Rep. 2019 May 28;27(9):2690-2708.

Growth Factors Group

Joaquín Arribas
Principal Investigator
Biosketch
Principal Investigator Joaquín Arribas Post-Doctoral Fellows Enrique Javier Arenas, Cristina Bernado, Faiz Bilal, Beatriz Morancho, Irene Rius, Veronica Rodilla Graduate Students Luis Alfonso Garcia, Alejandro Martinez-Sabadell, Macarena Roman Students Jose Angel Palomeque, Daniel Fernando Pilco, Carlos Ramirez, Federica Zanotti Technicians Marta Escorihuela, Beatriz Martin, Antonio Miguel Luque

Summary

During 2019, we continued our research line on novel immune therapies by generating novel CARs (chimeric antigen receptors). With the knowledge accumulated during the development and characterization of bispecific antibodies, we have been able to efficiently develop our CARS that are directed against the p95HER2 protein; only present in some mammary and gastric tumors, and completely absent in normal tissues. Importantly, this project has been funded by the Spanish Association Against Cancer (AECC) for the next five years.

In addition, our ever-expanding platform of breast and pancreatic cancer patient-derived experimental models led to us establishing several fruitful collaborations with several national and international groups. These partnerships have enabled us to identify novel mechanisms of resistance to anti-cancer therapies (Lambies et al., Diaz-Rodriguez et al., and Gomez-Miragaya et al.) as well as biomarkers of sensitivity to precision medicines (Kang et al., and Blasco-Benito et al.).

Our group has also contributed to the characterization of a novel antibody drug conjugate that is effective against some pancreatic tumors and triple negative breast cancers (Merlino et al.). Finally, we have also collaborated in identifying drugs targeting senescent cells which, under certain circumstances, majorly contribute to tumor progression. At VHIO, we have worked with several groups on research led by Sandra Peiró, Principal Investigator of our Chromatin Dynamics in Cancer Group, to unveil mechanisms that govern gene expression in triple negative breast cancer (Cebria Costa et al.).

Our highly collaborative approach has also allowed us to participate in several large-scale projects funded by the European Union this year, including the Immune-Image project supported by the Innovative Medicines Initiative (IMI). This large-scale consortium aims to develop novel tracers to monitor the immune response to anti-tumor therapies for research into patient-derived cancer xenografts. We are also participating in the COLOSSUS multi-center European Commission Horizon 2020-supported project; Advancing a Precision Medicine Paradigm in metastatic Colorectal Cancer: Systems based patient stratification solutions, for which our group is developing humanized mouse models.

Mention must also be made regarding the continued backing and support received from the Breast Cancer Research Foundation (BCRF), for which we are extremely grateful.

Several of our young talents have been awarded in 2019 including Veronica Rodilla who received a Stop Fuga de Cerebros grant from Roche, and Irene Rius and Faiz Bilal who defended their PhD theses on novel therapies against breast and pancreatic cancers, respectively.

Lastly, it has been an extremely productive year for the Centro de Investigación Biomédica en Red (CIBER-ONC: Center for the Biomedical Research Network in Oncology), under the scientific direction of our Principal Investigator, Joaquín Arribas. This recently established network is comprised of several of the most active cancer research groups across Spain, including three at VHIO.


Strategic goals

  • Generation and characterization of CARs against a subset of HER2 positive tumors.
  • Development of an ADC against p95HER2.
  • Determine the role of cellular senescence in breast cancer progression and treatment.
  • Identification of new mechanisms of resistance to targeted therapies against pancreatic cancer.

Highlights

  • We have initiated the development of a novel T-cell based therapy against p95HER2 positive breast cancer, p95HER2-CARs.
  • Our group has characterized mechanisms of resistance against anti-HER2 therapies in breast cancer.
  • We have identified novel factors implicated in pancreatic cancer resistance to MEK inhibitors.
  • We have collaborated in the characterization of novel senolytic compounds.

Horizons

  • To identify mechanisms of resistance to targeted therapies in pancreatic cancer.
  • Develop novel methods to redirect lymphocytes against breast cancer.
  • Improve the effect of antibody drug conjugates.

PI paper pick

  • Triana-Martínez F, Picallos-Rabina P, Da Silva-Álvarez S, Pietrocola F, Llanos S, Rodilla V, Soprano E, Pedrosa P, Ferreirós A, Barradas M, Hernández-González F, Lalinde M, Prats N, Bernadó C, González P, Gómez M, Ikonomopoulou MP, Fernández-Marcos PJ, García-Caballero T, Del Pino P, Arribas J, Vidal A, González-Barcia M, Serrano M, Loza MI, Domínguez E, Collado M. Identification and characterization of Cardiac Glycosides as senolytic compounds. Nat. Commun. 2019 Oct 21;10(1):4731.
  • Blasco-Benito S, Moreno E, Seijo-Vila M, Tundidor I, Andradas C, Caffarel MM, Caro-Villalobos M, Urigüen L, Diez-Alarcia R, Moreno-Bueno G, Hernández L, Manso L, Homar-Ruano P, McCormick PJ, Bibic L, Bernadó Morales C, Arribas J, Canals M, Casadó V, Canela EI, Guzmán M, Pérez-Gómez E, Sánchez C. Therapeutic targeting of HER2-CB2R heteromers in HER2-positive breast cancer. Proc Natl Acad Sci U S A. 2019 Feb 26;116(9):3863-3872.
  • Kang SA, Guan JS, Tan HJ, Chu T, Thike AA, Bernadó Morales C, Arribas J, Wong CY, Tan PH, Gudi M, Putti TC, Sohn J, Lim SH, Lee SC, Lim YP. Elevated WBP2 expression in HER2-positive breast cancers correlates with sensitivity to trastuzumab-based neo-adjuvant therapy:A Retrospective and Multicentric Study. Clin. Cancer Res. 2019 Apr 15;25(8):2588-2600.
  • Lambies G, Miceli M, Martínez-Guillamon C, Olivera-Salguero R, Peña R, Frías CP, Calderón I, Atanassov BS, Dent SYR, Arribas J, García de Herreros A, Díaz VM. TGFβ-activated USP27X deubiquitinase regulates cell migration and chemoresistance via stabilization of Snail1. Cancer Res. 2019 Jan 1;79(1):33-46.

Full list of Publications

  1. Triana-Martínez F, Picallos-Rabina P, Da Silva-Álvarez S, Pietrocola F, Llanos S, Rodilla V, Soprano E, Pedrosa P, Ferreirós A, Barradas M, Hernández-González F, Lalinde M, Prats N, Bernadó C, González P, Gómez M, Ikonomopoulou MP, Fernández-Marcos PJ, García-Caballero T, Del Pino P, Arribas J, Vidal A, González-Barcia M, Serrano M, Loza MI, Domínguez E, Collado M. Identification and characterization of Cardiac Glycosides as senolytic compounds. (2019) Nat Commun. 10(1):4731. doi: 10.1038/s41467-019-12888-x.
  2. Cebrià-Costa , J. P., Pascual-Reguant, L., Gonzalez-Pérez ,A., Serra-Bardenys , G., Querol , J., Cosin, M., Verde, G., Cigliano, RA., Sanseverino, W., Segura-Bayona S, Iturbide A, Andreu , D., Nuciforo, P., Bernadó-Morales, C.,  Rodilla V, Arribas, J., Yelamos J, de Herreros, A.G, Stracker TH, Peiró S. LOXL2-mediated H3K4 oxidation reduces chromatin accessibility in triple negative breast cancer cells.  (2019) Oncogene. 2019 Aug 28. doi: 10.1038/s41388-019-0969-1.
  3. Gomez-Miragaya, J., Díaz-Navarro, A., Tonda, R., Beltran, S., Palomero, L., Palafox, M., Dobrolecki, L., Vasaikar, S., Huang, C., Zhang, B., Wulf, G., Muñoz, P., Paré, L., Serra, V., Prat, A., Bruna, A., Caldas, C., Arribas, J., Balmaña, J., Cruz, C., Pujana, M. A., Lewis, M., Puente, X., Gonzalez-Suarez, E. Chromosome 12p amplification in triple-negative breast cancer is associated with emergent docetaxel resistance and carboplatin sensitivity (2019) Cancer Research79, 4258-4270.
  4. Merlino, G., Fiascarelli, A., Bigioni, M., Bressan, A., Carrisi, C., Bellarosa, D., Salerno, M., Bugianesi, R., Manno, R., Bernadó Morales, C., Arribas, J., Dusek, R. L., Pham, P. H., Awdew, R., Aud, D. M., Trang, M., Terrett, J., Wilson, K. E., Rohlff, C., Manzin, S., Pellacani, A, Binaschi, M. MEN1309/OBT076, a first-in-class Antibody Drug Conjugate (ADC) targeting CD205 in solid tumors (2019) Mol Cancer Ther. 2019 Sep;18(9):1533-1543.
  5. Diaz-Rodriguez, E., Pérez-Peña, J., Ríos-Luci, C., Arribas, J., Ocaña, A., Pandiella, A. TRAIL receptor activation overcomes resistance to trastuzumab in HER2 positive breast cancer cells (2019) Cancer Letters 453, 34-44.
  6. Gorbatenko, A., Søkilde, R., Sorensen, E. E., Newie, I., Persson, H., Morancho, B., Arribas, J., Litman, T., Rovira, C., Pedersen, S. F. HER2 and p95HER2 differentially regulate miRNA expression in MCF-7 breast cancer cells and downregulate MYB proteins through miR-221/222 and miR-503 (2019) Scientific Reports 9, 3352.
  7. Blasco-Benito S, Moreno E, Seijo-Vila M, Tundidor I, Andradas C, Caffarel MM, Caro-Villalobos M, Urigüen L, Diez-Alarcia R, Moreno-Bueno G, Hernández L, Manso L, Homar-Ruano P, McCormick PJ, Bibic L, Bernadó Morales C, Arribas J, Canals M, Casadó V, Canela EI, Guzmán M, Pérez-Gómez E, Sánchez C. Therapeutic targeting of HER2-CB2R heteromers in HER2-positive breast cancer. (2019) Proc Natl Acad Sci U S A. 116(9) 3863-3872.
  8. Kang SA, Guan JS, Tan HJ, Chu T, Thike AA, Bernadó Morales C, Arribas J, Wong CY, Tan PH, Gudi M, Putti TC, Sohn J, Lim SH, Lee SC, Lim YP. Elevated WBP2 expression in HER2-positive breast cancers correlates with sensitivity to trastuzumab-based neo-adjuvant therapy:A Retrospective and Multicentric Study. Clin Cancer Res. 2019 Apr 15;25(8):2588-2600.
  9. Lambies G, Miceli M, Martínez-Guillamon C, Olivera-Salguero R, Peña R, Frías CP, Calderón I, Atanassov BS, Dent SYR, Arribas J, García de Herreros A, Díaz VM. TGFβ-activated USP27X deubiquitinase regulates cell migration and chemoresistance via stabilization of Snail1. (2019) Cancer Res. 2019 Jan 1. 79(1):33-46.

Projects

  1. Redirection of T cells against HER2-driven tumors.
    Asociación Española Contra el Cáncer (AECC). Grupos Coordinados AECC 2019.
    Coordinator: Joaquín Arribas
    2019-2024
  2. Immunotherapy against HER2 positive tumors. PI19/01181.
    Instituto Salud Carlos III (ISCIII).
    PI: Joaquín Arribas
    2020-2022
  3. Novel therapies against HER2-positive breast tumors: targeting oncogene-induced senescence and the immune system. BCRF-19-08. Breast Cancer Research Foundation (BCRF).
    PI Joaquín Arribas
    2019-2020
  4. Conjugados Anticuerpo-Droga contra HER2: Mecanismos de Resistencia y Combinaciones Terapéuticas.
    Fundación Mutua Madrileña.
    Co-PIs: Joaquín Arribas, Javier Cortés.
    2018-2021
  5. 754923. Horizon 2020 call SC1-PM-02-2017. Consortium 14 Partners.
    Coordinator: Annette Byrne.
    PI: Joaquín Arribas.
    2018-2023
  6. EDIReX: EurOPDX Distributed Infrastructure for Research on patient-derived cancer Xenografts. 731105. Horizon 2020 call H2020-INFRAIA 2016-2017.
    Consortium 19 Partners.
    Coordinator: Enzo Medico.
    PI: Joaquín Arribas.
    2018-2022
  7. Immunotherapy Against HER2-positive Breast and Gastric Cancers. PI16/00253. Instituto de Salud Carlos III.
    PI: Joaquín Arribas.
    2017-2019
  8. Novel therapies against HER2-positive breast tumors: targeting oncogene-induced senescence and the immune system. BCRF-18-008. Breast Cancer Research Foundation (BCRF).
    PI: Joaquín Arribas. 2018-2019
  9. Immunotherapy against p95HER2 positive breast cancer. 2016 PROD 00108. Fondos Europeos de Desarrollo Regional (FEDER) 2014-2020/Agencia de Gestió d’Ajuts Universitaris i de Recerca (AGAUR).
    PI: Joaquín Arribas.
    2017-2019
  10. CB16/12/00449. Instituto de Salud Carlos III.
    PI: Joaquín Arribas.
    2017-2020.

Mouse Models of Cancer Therapies Group

Laura Soucek
Principal Investigator
Biosketch
Principal Investigator Laura Soucek Staff Scientist Jonathan Whitfield Post-Doctoral Fellows Jastrinjan Kaur, Mariano F. Zacarias Graduate Student Sandra Martinez Technicians Virginia Castillo, Inmaculada Genesis Martin, Erika Serrano del Pozo Fulbright Scholar Jessica Lee Chambers

Summary

Our group focuses on the pleiotropic and ubiquitous Myc oncoprotein, whose deregulation is implicated in almost all human cancers. The technical challenges of targeting nuclear transcription factors such as Myc –and the concern regarding potential side effects– had until recently precluded any preclinical validation of Myc inhibition as a possible therapeutic strategy.

Over the past few years, we have demonstrated in several mouse models that Myc inhibition has a dramatic therapeutic impact across several tumor types, with very mild and reversible side effects in normal tissue.

Encouraged by our results in mice, we are now interested in developing viable, non-toxic pharmacological options for Myc targeting in the clinic. To do so, we have created a spin-off company, Peptomyc S.L., for the development of Myc-inhibiting peptides for cancer therapy. Our laboratory in partnership with Peptomyc is currently validating our novel approach against notoriously difficult-to-treat cancers that are resistant to standard treatments and in dire need of new therapeutic avenues (i.e. KRAS-driven Non-Small Cell Lung Cancer, glioblastoma, and metastatic triple negative breast cancer).

Our group has continued to contribute to groundbreaking science by publishing in journals of international prestige. One particular highlight for 2019 is a paper describing key studies for advancing our Myc inhibitor mini-protein Omomyc towards the clinic (Beaulieu et al. Intrinsic cell-penetrating activity propels Omomyc from proof of concept to viable anti-Myc therapy. Sci Trans Med. 2019). This publication was very well received by the scientific community and highlighted in Nature Reviews Cancer and Nature Reviews Drug Discovery as a potential seminal milestone towards the clinical application of our first-in-class Myc inhibitor.

Laura Soucek and first author Marie-Eve Beaulieu also had the opportunity to add their authors’ views regarding this important achievement thanks to a publication in Molecular & Cellular Oncology, in which they summarized the main take-home messages of their publication in Science Translational Medicine on Myc biology and inhibition.

This year has also celebrated several collaborative successes:

Our work with Rajeev Vibhakar’s laboratory led to a publication in International Journal of Cancer, demonstrating the therapeutic potential of Myc inhibition in childhood rhabdoid tumors. In addition, results of our collaborative studies with teams led by Esther Vazquez, Ibane Abasolo and Antonio Villaverde, were published in Advanced Science and demonstrate the potential of therapeutic proteins delivered in the form of inclusion bodies to treat breast cancer.

Last but not least, we contributed to an excellent manuscript headed by Jordi Alcaraz and published in Cancer Research, showing that epigenetic SMAD3 repression in tumor-associated fibroblasts reduces fibrosis and sensitivity to the antifibrotic drug nintedanib in lung squamous cell carcinoma.

We have also had the privilege of hosting a Fulbright Scholar (as part of the U.S. Department of Education’s International Exchange Program), Jessica Chambers, who graduated from Princeton University.


Strategic goals

  • Validation of new Omomyc-based cell penetrating peptides for cancer therapy.
  • Preclinical validation of novel anti-Myc therapies in breast, brain, lung, neuroblastoma, melanoma, colorectal cancer and multiple myeloma.
  • Define the role of Myc in promoting cancer immune evasion.
  • Elucidate the role of the Myc network in Max-defective gastrointestinal stromal tumors (GISTs), Small-Cell Lung Cancer (SCLC) and Pheochromocytomas (PCC).

Highlights

  • The publication by Beaulieu et al. in Science Translational Medicine showing that the Myc inhibitory peptide Omomyc can penetrate cancer cells and act against tumors in vivo, demonstrating its potential for clinical development, has generated a great deal of media coverage.
  • Laura Soucek and Jonathan Whitfield were guest editors of a special edition of Current Opinion in Pharmacology on Peptides in Cancer.
  • Additional new funding granted, notably from La Marató and FIS (ISCIII).
  • 2 new patent applications were filed by Laura Soucek’s laboratory.

Horizons

  • Advance the discovery and validation of novel therapies for cancer treatment, especially against difficult-to-target proteins such as Myc.
  • Additional focus continues to center on the role of Myc in promoting cancer immune evasion and potential actionable targets and therapeutic strategies in this context.

Awards and Recognition

  • As a key opinion leader in Myc and cancer, Laura Soucek was invited to write reviews, be guest editor for a special edition of Current Opinion in Pharmacology, and assemble an updated version of the Springer Nature Methods in Molecular Biology series book on Myc protocols.
  • She has also been appointed as Member of the Scientific Committee of the FERO Foundation, Spain.
  • Her scientific and entrepreneurial merits have also been recognized by the sportswear/equipment brandNIKEin Barcelona that selected her and Marie-Eve Beaulieu (first author of the Science Translational Medicinepaper in 2019) as model talents for science for the launch of their most recent FC Barcelona strip and merchandize campaign 2019.
  • Finally, Laura was presented with the European Award for Female Entrepreneurs by the Asociación Europea de Economía y Competitividadand won the FIDEM Award (International Foundation for Women Entrepreneurs) under the category for science.

PI paper pick

  • Beaulieu ME, Jauset T, Massó-Vallés D, Martínez-Martín S, Rahl P, Maltais L, Zacarias-Fluck MF, Casacuberta-Serra S, Serrano del Pozo E, Fiore C, Foradada L, Castillo Cano V, Guenther M, Romero Sanz E, Oteo M, Tremblay C, Martín G, Letourneau D, Montagne M, Morcillo Alonso MA, Whitfield JR, Lavigne P, Soucek L. Intrinsic cell-penetrating activity propels Omomyc from proof of concept to viable anti-Myc therapy. Sci Trans Med. 2019 Mar 20;11(484).
  • Beaulieu ME, Soucek L. Finding MYCure. Mol Cell Oncol. 2019 Jun 20;6(5):e1618178.
  • Pesarrodona M, Jauset T, Díaz-Riascos ZV, Sánchez-Chardi A, Beaulieu ME, Seras-Franzoso J, Sánchez-García L, Baltà-Foix, Sandra Mancilla R, Fernández Y, Rinas U, Schwartz Jr S, Soucek L, Villaverde A, Abasolo I, Vázquez E. Targeting antitumoral proteins to breast cancer by local administration of functional inclusion bodies. Adv Sci. 2019 Jul 24.
  • Whitfield JR, Soucek L. Editorial Overview: Peptides in Cancer. Curr Opin Pharmacol. 2019 Jun 27. pii: S1471-4892(19)30045-1.

Full list of Publications

  1. Ikemori R, Gabasa M, Duch P, Vizoso M, Bragado P, Arshakyan M, Luis IC, Marín A, Morán S, Castro M, Fuster G, Gea-Sorli S, Jauset T, Soucek L, Montuenga LM, Esteller M, Monsó E, Peinado VI, Gascon P, Fillat C, Hilberg F, Reguart N, Alcaraz J. Epigenetic SMAD3 Repression in Tumor-Associated Fibroblasts Impairs Fibrosis and Response to the Antifibrotic Drug Nintedanib in Lung Squamous Cell Carcinoma. Cancer Res. 2019 Nov 6.
  2. Pesarrodona M, Jauset T, Díaz-Riascos ZV, Sánchez-Chardi A, Beaulieu ME, Seras-Franzoso J, Sánchez-García L, Baltà-Foix R, Mancilla S, Fernández Y, Rinas U, Schwartz Jr S, Soucek L, Villaverde A, Abasolo I, Vázquez E. Targeting antitumoral proteins to breast cancer by local administration of functional inclusion bodies. Adv Sci.  2019 Jul 24.
  3. Whitfield JR, Soucek L. Editorial Overview: Peptides in Cancer.  Curr Opin Pharmacol. 2019 Jun 27. pii: S1471-4892(19)30045-1.
  4. Ramón Y Cajal S, Sancho P, Soucek L, Peinado H, Abad M, Valiente M, Efeyan A, Pardo J, Quesada V, Jimeno J, Duque PM, Antón A, Varela I, Schuhmacher AJ. A spotlight on cancer researchers in Spain: new paradigms and disruptive ideas. Clin Transl Oncol. 2019 Aug 9.
  5. Beaulieu ME, Jauset T, Massó-Vallés D, Martínez-Martín S, Rahl P, Maltais L, Zacarias-Fluck MF, Casacuberta-Serra S, Serrano del Pozo E, Fiore C, Foradada L, Castillo Cano V, Guenther M, Romero Sanz E, Oteo M, Tremblay C, Martín G, Letourneau D, Montagne M, Morcillo Alonso MA, Whitfield JR, Lavigne P, Soucek L.  Intrinsic cell-penetrating activity propels Omomyc from proof of concept to viable anti-Myc therapy.Sci Trans Med.2019 Mar 20;11(484).
  6. Alimova I, Pierce A, Danis E, Donson A, Birks DK, Griesinger A, Foreman NK, Santi M, Soucek L, Venkataraman S, Vibhakar R. Inhibition of MYC attenuates tumor cell self-renewal and promotes senescence in SMARCB1 deficient Group 2 Atypical Teratoid Rhabdoid Tumors to suppress tumor growth in vivo.Int J Cancer. 2019 Apr 15;144(8):1983-1995.

Projects

  1. Instituto de Salud Carlos III: Proyectos FIS de Investigación en Salud.
    Title: Validation of new anti-Myc therapy in Melanoma. 2020-2023.
    PI: Laura Soucek
    Awarded in 2019.
  2. Fundació La Marató de TV3.
    Title: Overcoming immunotherapeutic resistance through Myc inhibition in KRas-driven NSCLC with diverse mutational landscape.
    2020-2022.
    Project Director: Laura Soucek. Co-participant: Silvestre Vicent Cambra.
    Awarded in 2019.
  3. Canadian Institutes of Health Research Grant.
    Title:Development of cancer therapies targeting Myc with cell penetrating b-HLH-LZ domains.
    2018-2023.
    Role: Co-applicant.
  4. ERC (European Commission) Proof-of-Concept Grant.
    Title: Development of an effective and safe systemic Myc inhibitor for the treatment of multiple cancer types.
    2017-2019.
    PI: Laura Soucek
  5. H2020 INFRAIA 2017
    Grant: EDIReX: EurOPDX Distributed Infrastructure for Research on patient-derived cancer Xenografts.
    2017-2021.
    Role: Co-applicant
  6. Instituto de Salud Carlos III: Proyectos FIS de Investigación en Salud.
    Title: In vivo validation of innovative anti-Myc therapies in glioblastoma. 2016-2019.
    PI: Laura Soucek

Stem Cells & Cancer Group

Héctor G. Palmer
Principal Investigator
Biosketch
Principal Investigator Héctor G. Palmer Post-Doctoral Fellows Oriol Arques, Estefania Cuesta, Jordi Martinez-Quintanilla, Isabel Puig Graduate Student Alex Mur Technicians Laia Cabellos, Irene Chicote, Lorena Ramirez Student Claudia Bigas

Summary

Hector G. Palmer and his Stem Cells & Cancer Group are studying the mechanisms that permit tumors to escape from effective treatments and progress to advanced stages, when patients’ lives are at risk.

His team uses multi-omic approaches for revealing unexpected alterations related with tumor phenotypes. The group also pairs gene editing (CRISPR/Cas) with classical signalling biochemistry in cancer cell lines as well as genetically modified mice, patient-derived organoids and xenografts (PDX) to study the functional relevance of these newly identified alterations in patients' response to therapies.

The group is also part of a global multidisciplinary task force that includes oncologists, surgeons, radiologists and nurses. This strong collaboration means that laboratory results have a rapid clinical interpretation and translation to the bedside.

Main research lines include:

Tumor cell dormancy

We study the intriguing biology of cancer cell dormancy that is responsible for chemoresistance, formation of minimal residual disease and relapse of patients. The team discovered a core epigenetic network governing dormancy of tumor cells (J Clin Invest. 2018), and is now studying the function of TET2, DPPA3 and other epigenetic factors governing dormancy in further depth. Importantly, we are rapidly progressing in developing drugs that modulate dormancy drivers including TET2 and defining novel biomarkers to detect chemo-resistant dormant tumor cells (DTC).

Response to target-directed drugs

Our group works in close collaboration with oncologists and pharmaceutical companies to identify molecular mechanisms responsible for the sensitivity or resistance to drugs blocking Wnt/beta-catenin, Notch, PI3K/AKT, EGFR/LGR5 or BRAF/MEK/ERK oncogenic signals (Nat Med. 2012; Clin Can Res. 2014; Clin Can Res. 2019). Based on our discoveries we are designing new pre-screening tests for a genetic-guided enrolment of patients in clinical trials. Crucially, our findings are helping to define new rational drug combinations to treat cancer patients with progressive disease.

Advanced pre-clinical models of cancer

We are expanding and characterizing our PDX collections (CRC, neuroendocrine, hepatic tumors and peritoneal pseudomyxoma), and improving their potential to evaluate drug efficacy and metastasis by orthotopic injection and live imaging (TC, PET and Echography).

We are developing ambitious projects through the EuroPDX Consortium, a collaboration that VHIO co-founded incorporating the main reference groups working with PDX in Europe.


Strategic goals

  • Understanding Tumor Dormancy Studying the role of epigenetic factors ruling dormancy in chemoresistance, minimal residual disease, relapse, dissemination and metastasis.
  • ONIRIA - modulating cell dormancy to fight cancer Developing small drugs modulators of cancer cell dormancy to block cancer progression.
  • Matching targeted therapies Revealing the mechanisms of response to drugs targeting EGFR, BRAF, MEK, ERK, LGR5, Wnt or PARP.
  • Refining advanced cancer models Expanding our collection of PDXs and developing new orthotopic models and live imaging techniques.

Highlights

  • Cancer cell dormancy We have revealed key epigenetic factors ruling cancer cell dormancy, hypoxia, chemoresistance and tumor recurrence and developed effective small drugs targeting some of them.
  • Matched therapies Our group has described relevant determinants of response to BRAF and Notch inhibitors, and demonstrated the efficacy of new rational drug combinations and evaluated the minimal residual disease of RET fused tumors.
  • Advanced cancer models We have generated and refined new cancer models of colorectal cancer in collaboration with several European funded networks.

Horizons

  • ONIRIA Spin off We are committed to creating a spin off company to develop drug modulators of cancer cell dormancy as a new strategy to fight cancer. We have already developed lead compounds that activate TET2 and show anti-tumoral activity. To achieve this ambitious challenge, we have set up a collaboration that includes experts in drug development with experience in similar projects. Importantly, ONIRIA will be hosted by VHIO given its successful track record in spin off companies, and promoted by our team as experts in investigating first-in-class drugs in partnership with VHIO’s clinical investigators with a solid background in early phase clinical studies.
  • Revealing new drivers of cancer cell dormancy. We aim to demonstrate the relevance of different epigenetic or transcription factors as master regulators of DTC distinctive phenotype. Specifically, we hope to publish our findings on DPPA3 as crucial factor in hypoxia and chemoresistance. Other drivers governing dormancy are currently under investigation by one of our postdoctoral fellows and two students as part their thesis and Masters degrees, respectively. Since this research line is technically complex and relatively unexplored, the challenge that we face is to make a significant contribution to the understanding of cancer cell dormancy and chemoresistance. We aim to reveal future drug targets and biomarkers to eradicate and identify DTC and reducing chemoresistance and risk of patients´ relapse.
  • Defining new effective therapies based on rational drug combinations. Based on our discoveries in new mechanisms of resistance to EGFR, BRAF, MEK, Wnt, Notch, RET, LGR5 or PARP inhibitors, we will design and test novel drug combinations that could benefit patients whose disease has progressed on initial treatments. This approach, based on analyses of paired patients’ tumor samples and PDX models treated with matched therapies, already shows great promise. We therefore expect to report new insights into the mechanisms of action of some targeted drugs that will guide oncologists to design and test more precise and effective treatments.
  • Innovating in pre-clinical cancer models. One of our challenges is to integrate several imaging techniques (TC, PET and echography) for the longitudinal evaluation of mice orthotopically implanted with patient-derived cells and follow their response to new drug combinations. These comprehensive models could be more faithful in recapitulating advanced cancer in patients and therefore become a powerful tool in translating our laboratory results to the clinic.

PI paper pick

  • Capdevila J, Arqués O, Hernández Mora JR, Matito J, Caratù G, Mancuso FM, Landolfi S, Barriuso J, Jimenez-Fonseca P, Lopez Lopez C, Garcia-Carbonero R, Hernando J, Matos I, Nuciforo P, Hernández-Losa J, Esteller M, Martínez-Cardús A, Tabernero J, Vivancos A, Palmer HG. Epigenetic EGFR Gene Repression Confers Sensitivity to Therapeutic BRAFV600E Blockade in Colon Neuroendocrine Carcinomas. Clin Cancer Res. 2020 Feb 15;26(4):902-909. doi: 10.1158/1078-0432.CCR-19-1266. Epub 2019 Oct 31.
  • Capdevila J, Matos I, Mancuso FM, Iglesias C, Nuciforo P, Zafon C, Palmer HG, Ogbah Z, Muiños L, Hernando J, Villacampa G, Peña CE, Tabernero J, Brose MS, Schlumberger M, Vivancos A. Identification of Expression Profiles Defining Distinct Prognostic Subsets of Radioactive-Iodine Refractory Differentiated Thyroid Cancer from the DECISION Trial. Mol Cancer Ther. 2020 Jan;19(1):312-317. doi: 10.1158/1535-7163.MCT-19-0211. Epub 2019 Sep 20.
  • Selenica P, Raj N, Kumar R, Brown DN, Arqués O, Reidy D, Klimstra D, Snuderl M, Serrano J, Palmer HG, Weigelt B, Reis-Filho JS, Scaltriti M. Solid pseudopapillary neoplasms of the pancreas are dependent on the Wnt pathway. Mol Oncol. 2019 Aug;13(8):1684-1692. doi: 10.1002/1878-0261.12490. Epub 2019 Jul 3.

Full list of Publications

  1. Capdevila J, Arqués O, Hernández Mora JR, Matito J, Caratù G, Mancuso FM, Landolfi S, Barriuso J, Jimenez-Fonseca P, Lopez Lopez C, Garcia-Carbonero R, Hernando J, Matos I, Paolo N, Hernández-Losa J, Esteller M, Martínez-Cardús A, Tabernero J, Vivancos A, Palmer HG. Epigenetic EGFR Gene Repression Confers Sensitivity to Therapeutic BRAFV600E Blockade in Colon Neuroendocrine Carcinomas.Clin Cancer Res. 2020 Feb 15;26(4):902-909. doi: 10.1158/1078-0432.CCR-19-1266. Epub 2019 Oct 31.
  2. Capdevila J, Matos I, Mancuso FM, Iglesias C, Nuciforo P, Zafon C, Palmer HG, Ogbah Z, Muiños L, Hernando J, Villacampa G, Peña CE, Tabernero J, Brose MS, Schlumberger M, Vivancos A. Identification of Expression Profiles Defining Distinct Prognostic Subsets of Radioactive-Iodine Refractory Differentiated Thyroid Cancer from the DECISION Trial.Mol Cancer Ther. 2020 Jan;19(1):312-317. doi: 10.1158/1535-7163.MCT-19-0211. Epub 2019 Sep 20.
  3. Selenica P, Raj N, Kumar R, Brown DN, Arqués O, Reidy D, Klimstra D, Snuderl M, Serrano J, Palmer HG, Weigelt B, Reis-Filho JS, Scaltriti M. Solid pseudopapillary neoplasms of the pancreas are dependent on the Wnt pathway.Mol Oncol. 2019 Aug;13(8):1684-1692. doi: 10.1002/1878-0261.12490. Epub 2019 Jul 3.

Projects

  1. Accelerator Award. Pseudomyxoma peritonei: building a European multicentric cohort to accelerate new therapeutic perspectives.
    Funding entities: Cancer Research UK (CRUK), Asociación Española contra el Cancer (AECC) & Associazione Italiana per la Ricerca sul Cancro (AIRC).
    2019-2024.
    PI: Héctor G. Palmer (Consortium Coordinator: Marcello Deraco).
  2. SCITRON. Discovering Mechanisms of Resistance to Anti-BRAFV600E-based therapies.
    Funding entity:Novartis International AG.
    2018-2020.
    PI: Héctor G. Palmer.
  3. ONIRIA: Modulating Cell Dormancy to Fight Cancer.
    Funding entity:Fundación Bancaria Caixa d’Estalvis i Pensions de Barcelona.
    2019-2020.
    PI: Héctor G. Palmer.
  4. Accelerator Award. ACRCelerate: Colorectal Cancer Stratified Medicine Network.
    Funding entities: Cancer Research UK (CRUK), Asociación Española contra el Cáncer (AECC) & Associazione Italina per la Ricerca sal Cancro (AIRC).
    2018-2021.
    PI: Héctor G. Palmer (Consortium Coordinator: Owen Sansom).
  5. Eider, EurOPDX Distributed Infrastructure for Research on patient-derived cancer Xenografts.
    Funding entity: EU Horizon2020 Research and Innovation Program.
    2018-2021.
    PI: Héctor G. Palmer (Consortium Coordinator: Enzo Medico).
  6. Studying the efficacy of BLU667 on axenograft model of papillary thyroid carcinoma with a NCOA4-RETfusion.
    Funding entity: Blueprint.
    2018-2020.
    PI: Héctor G. Palmer.
  7. Funding entity: Fundación de la Asociación Española Contra el Cáncer (AECC).
    2017-2021.
    PIs: Isabel Puig and Héctor G. Palmer.
  8. Anti-LGR5/EGFR bi-specific antibodies for the treatment of mCRC.
    Funding entity: MERUS.
    2016-2020.
    PI: Héctor G. Palmer.
  9. Cáncer de colon hipermutante - de su génesis y evolución genética a los tratamientos dirigidos contra dianas moleculares. PI17/00945.
    Funding entity: Instituto de Salud Carlos III.
    2016-2020.
    PI: Héctor G. Palmer.
  10. Refining mesothelin as therapeutic target in advanced colorectal cancer.
    Funding entity: Bayer Global.
    2017-2020.
    PIs: Héctor G. Palmer and Paolo Nuciforo.

Tumor Biomarkers Group

Josep Villanueva
Principal Investigator
Biosketch
Principal Investigator Josep Villanueva Post-Doctoral Fellows Chiara Bellio Olga Méndez, Nathalie Meo-Evoli Graduate Student Mireia Pujals Technicians Mireia Pares, Candida Salvans, Gabriel Tamayo

Summary

Tumor cell communication with its microenvironment plays an important role in tumor initiation and progression. Cancer cells hijack the tumor microenvironment ecosystem via paracrine signaling to promote a pro-oncogenic microenvironment that is crucial for the development of primary and metastatic tumors.

Our main aim is to characterize the mechanisms adopted by these cells to communicate amongst themselves as well as with their microenvironment during tumorigenesis. We aim to exploit these data to advance biomarker and drug target discovery.

Our team’s working hypothesis is that cellular signaling pathways undergo alterations during the tumorigenesis process and that these changes are translated into differential protein secretion, which can also potentially be used to identify secreted markers. Furthermore, some of the differentially regulated proteins could be direct extracellular messengers of intracellular signaling pathways contributing to fundamental stages implicated in cancer initiation and progression, therefore representing potential therapeutic targets.

The methodological focus of our group centers on profiling the secreted sub-proteome (‘secretome’) of cells by quantitative mass spectrometry. Most secreted proteins contain a signal peptide that directs their sorting to the extracellular space through the endoplasmic reticulum (ER)–Golgi secretory pathway. One of the most striking observations when secretome profiles are carefully produced and analyzed is that they contain hundreds of theoretical intracellular proteins.

Recent reports showing intracellular proteins with alternative extracellular functions suggest that new protein functions associated with alternative subcellular localizations could implicated in tumorigenesis. In line with this notion, our recent efforts within the context of therapeutics and tumor invasion have led us to hypothesize that the characterization of non-classical protein secretion could lead to the development of novel anti-cancer therapies.


Strategic goals

  • Exploit the role of non-classical secretion linked to tumor invasion and metastasis to identify biomarkers and therapeutic targets against breast cancer.
  • Characterize the role of extracellular HMGA1 in breast cancer invasion and metastasis.
  • The characterization of mechanisms adopted by tumor cells to communicate with their microenvironment during treatment to establish secreted response/resistance biomarkers to cancer drug therapies.

Highlights

  • We have recently generated monoclonal antibodies (mAbs) against HMGA1 and now validating them in vitro. The results obtained using the antibodies in migration, invasion and cancer signaling assays are very promising. We foresee to continue validating them as biomarkers predicting metastasis in breast cancer, and as drugs that could block invasion and metastasis in Triple-Negative Breast Cancer (TNBC).

Horizons

  • One of our main goals is to better understand why Triple-Negative Breast Cancer (TNBC) becomes metastatic using a proteomics-based secretome approach. We aim to continue to reveal novel pathways such as HMGA1-RAGE as potentially new cancer drug targets.
  • We believe that we can improve outcomes for TNBC patients by exploiting the diagnostic and therapeutic capabilities of the cancer secretome. Our goal is to develop biomarkers and identify mechanisms of acquired resistance for current anti-cancer medicines.
  • We are in the final stages of validating HMGA1-mAbs in vitroas reagents to block the pro-invasive and pro-metastatic phenotypes of aggressive TNBC cells. We envision that these antibodies could be new therapeutic tools against this tumor type.

PI paper pick

  • Méndez O, Pérez J, Soberino J, Racca F, Cortés J, Villanueva J. Clinical Implications of Extracellular HMGA1 in Breast Cancer. Int J Mol Sci. 2019. 20(23), 5950.

Full list of Publications

  1. Méndez O, Pérez J, Soberino J, Racca F, Cortés J,  Villanueva J. Clinical Implications of Extracellular HMGA1 in Breast Cancer. Int J Mol Sci. 2019, 20(23), 5950.
  2. Arreal L, Piva M, Fernández S, Revandkar A, Schaub-Clerigué A, Villanueva J, Zabala-Letona A, Pujana M, Astobiza I, Cortazar AR, Hermanova I, Bozal-Basterra L, Arruabarrena-Aristorena A, Crespo JR, Valcarcel-Jimenez L, Zúñiga-García P, Canals F, Torrano V, Barrio R, Sutherland JD, Alimonti A, Martin-Martin N, Carracedo A.Targeting PML in triple negative breast cancer elicits growth suppression and senescence. Cell Death Differ. 2019 Oct 1. doi: 10.1038/s41418-019-0407-5.

Projects

  1. Characterization of HMGA1 as a mediator of tumor progression in breast cancer.
    Funding Agency: Pla estratègic de Recerca i Innovació en Salut (PERIS). Departament de Salut. Generalitat de Catalunya.
    Duration: 2017 – 2019.
    Recipient: Olga Méndez.
  2. Caracterización de HMGA1 como mediador de la progresión tumoral en el cáncer de mama.
    Funding Agency: Instituto de Salud Carlos III (ISCIII).
    Duration: 2016 – 2019.
  3. We are part of CIBERONC’s Programa de Tumores del Tracto Digestivo, as part of the group (Program ID: CB16/12/00259) led by VHIO’s Director and Head of our Gastrointestinal & Endocrine Tumors Group, Josep Tabernero (PI: Teresa Macarulla).