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 allows them to transit between different cellular states, including reversible transitions between mesenchymal and epithelial phenotypes, or between stem cell-like and differentiated states.
In 2013, we demonstrated that cellular plasticity can be induced in vivo, and somatic cells can dedifferentiate in the adult organism, even reaching pluripotency. Furthermore, we have demonstrated that tissue damage, the main driver of cancer, triggers cell dedifferentiation and the acquisition of stem cell properties.
Importantly, pluripotent stem cells and cancer cells manifest many parallels, and cellular reprogramming and neoplastic transformation are currently viewed as related processes governed by common molecular mechanisms. These observations strongly indicate that cellular plasticity and the acquisition of stem cell properties are important players in carcinogenesis. Moreover, they also bear important therapeutic implications given that chemotherapy and radiotherapy - the cornerstone 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 new therapies based on the inhibition of cancer cell plasticity.
Recent and surprising 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 identified to-date have been shown to play key functions in processes such as muscle performance, embryonic development and regeneration, opening a new level of complexity with tremendous implications, from basic research to the clinical setting. One of our objectives is to identify micropeptides involved in cancer stemness that could represent novel actors in carcinogenesis.
During 2017, we have made great progress: we have already identified 6 lncRNA-coded micropeptides, analyzed them in silico, and cloned them. We are currently performing an exhaustive functional characterization in vitro and in vivo. So far, we have compelling evidence that three of them act as novel tumor suppressors. The identification and characterization of novel micropeptides could be crucial in advancing insights into cancer physiopathology and better understanding the lack of success with current therapies. Moreover, they could serve as new cancer biomarkers for early detection and patient stratification for tailored therapies as well as therapeutic targets.
Figure: Working hypothesis by which cellular plasticity and the acquisition of stem cell properties are important players during tumor initiation, maintenance, as well as in tumor relapse after therapy. One of our objectives is to identify novel micropeptides involved in cancer cell plasticity which could offer new therapeutic opportunities.
Abad M, Hashimoto H, Zhou H, Morales MG, Chen B, Bassel-Duby R, Olson EN. Notch inhibition enhances cardiac reprogramming by increasing MEF2c transcriptional activity. Stem Cell Reports. 2017 Mar 14;8(3):548-560.
Marión RM, Lopez-de Silanes I, Mosteiro L, Gamache B, Abad M, Guerra C, Megías D, Serrano M, Blasco MA. Common telomere changes during in vivo reprogramming and early stages of tumorigenesis. Stem Cell Reports. 2017 Feb 14;8(2):460-475.
Gómez-Cabello D, Checa-Rodriguez C, Abad M, Serrano M, Huertas P. CtIP specific roles during cell reprogramming have long term consequences in iPSC survival and fitness. Stem Cell Reports. 2017 Feb 14;8(2):432-445.
Translational Research Coordinator
Clinical Research Coordinator
Juan Camilo Nieto
Biomedical research at VHIO's Experimental Hematology Group focuses on the translational study of hematological neoplasms of both lymphoid and myeloid origin.
We aim to decipher factors and mechanisms involved in the pathogenesis and progression of hematological malignancies by studying the molecular and microenvironmental mechanisms related to disease progression, response, and resistance to novel therapies, with particular emphasis on the cross-talk between malignant and healthy immune cells. Current projects include the study of chronic lymphocytic leukemia (CLL), diffuse large B cell lymphoma (DLBCL), and acute myeloid leukemia (AML).
Our group also explores new therapeutic avenues for patients diagnosed with hematological malignancies through the ex-vivo assessment of response to novel treatments, taking into account the microenvironmental protection that neoplastic cells found in lymphoid tissues and bone marrow. Over the last few years we have reported important insights into the role of the microenvironment in CLL natural history. This has enabled us to develop a highly reproducible and reliable pre-clinical model of CLL that recapitulates the favorable microenvironment using primary tumoral cells from patients.
We have also developed a PDX model for central nervous system lymphomas in collaboration with Joan Seoane, Director of Translational Research at VHIO and Principal Investigator of our Institute's Gene Expression and Cancer Group. Using this approach we study novel therapeutic options for patients in close collaboration with different pharmaceutical and biotech companies in order to drive new drugs to market, as well design a clinical trial for CNS lymphoma patients. In addition we are studying the role of novel targeted therapies in primary samples from patients with AML.
We are also committed to defining new biomarkers in hematology that will allow for a more rational and precise treatment of patients. These projects include the development of a genetic biomarker platform for lymphoproliferative malignancies through a combination of a customized Next Generation Sequencing panel of genes and detection of gene expression using Nanostring technology. Our group is also studying the role of circulating tumoral DNA detection in cerebrospinal liquid in CNS lymphomas in order to facilitate diagnosis and prediction of CNS relapse in a less invasive manner.
Lastly, we are initiating an ambitious project aimed at unmasking biomarkers of immune activation related to the clinical results of an allogeneic stem cell transplant.
Figure: Interaction between chronic lymphocytic leukemia cells and the tumoral immune microenvironment.
Our main purpose is to translate preclinical findings into clinical benefit through the development of early phase clinical trials and defining new prognostic and predictive factors.
Main research lines currently center on:
Abrisqueta P, Scott DW, Slack GW, Steidl C, Mottok A, Gascoyne RD, Connors JM, Sehn LH, Savage KJ, Gerrie AS, Villa D. Observation as the initial management strategy in patients with mantle cell lymphoma. Ann Oncol. 2017 Oct 1;28(10):2489-2495.
Purroy N, Carabia J, Abrisqueta P, Egia L, Aguiló M, Carpio C, Palacio C, Crespo M, Bosch F. Inhibition of BCR signaling using the Syk inhibitor TAK-659 prevents stroma-mediated signalingin chronic lymphocytic leukemia cells. Oncotarget. 2017 Jan 3;8(1):742-756.
Scott DW, Abrisqueta P, Wright GW, Slack GW, Mottok A, Villa D, Jares P, Rauert-Wunderlich H, Royo C, Clot G, Pinyol M, Boyle M, Chan FC, Braziel RM, Chan WC, Weisenburger DD, Cook JR, Greiner TC, Fu K, Ott G, Delabie J, Smeland EB, Holte H, Jaffe ES, Steidl C, Connors JM, Gascoyne RD, Rosenwald A, Staudt LM, Campo E, Rimsza LM; Lymphoma/Leukemia Molecular Profiling Project. New Molecular Assay for the Proliferation Signature in Mantle Cell Lymphoma Applicable to Formalin-Fixed Paraffin-Embedded Biopsies. J Clin Oncol. 2017 May 20;35(15):1668-1677.
Vitolo U, Trněný M, Belada D, Burke JM, Carella AM, Chua N, Abrisqueta P, Demeter J, Flinn I, Hong X, Kim WS, Pinto A, Shi YK, Tatsumi Y, Oestergaard MZ, Wenger M, Fingerle-Rowson G, Catalani O, Nielsen T, Martelli M, Sehn LH. Obinutuzumab or Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Previously Untreated Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2017 Nov 1;35(31):3529-3537.
Carlos Alberto Fajardo
The immune system can recognize and eliminate cancer. However, tumors evade the immune response through multiple mechanisms. Cancer immunotherapy exploits the immune system to attack disease. Clinical studies have established that immune checkpoint inhibitors and T cell-based therapies can mediate tumor regression in patients with metastatic cancer. Thus, in addition to surgery, radiation therapy and chemotherapy, immunotherapy has become the fourth pillar of anti-cancer therapy.
Despite encouraging antitumor responses, only a fraction of patients treated with immunotherapy respond and some develop autoimmune adverse events. There is thus a critical need to personalize these therapies. We are currently investigating mechanisms of response, toxicity and resistance to cancer immunotherapeutics in patients at the Vall d'Hebron University Hospital (HUVH). Our goal is to identify biomarkers of response to these therapies in liquid biopsies.
One of the correlative biomarkers of response to immunotherapy described to-date is mutation burden. Tumor-specific somatic mutations are optimal targets for cancer immunotherapy and render tumors immunogenic; some of these can bind to the patient's HLA molecules and elicit T-cell responses. Our group uses a highly personalized approach to screen for T-cell mediated recognition of mutated antigens as well as shared antigens using autologous antigen presenting cells that can process and present in all the potential HLA restriction elements. Following this strategy, we will explore whether the presence of lymphocytes recognizing these antigens is associated with response. In parallel, we plan to advance personalized T-cell therapies to treat metastatic colorectal cancer, which is largely resistant to current therapeutic strategies.
In summary, our group focuses on better understanding the naturally occurring T-cell response to cancer and establishing ways to exploit these antitumor responses to develop more effective, powerful, and precise immunotherapies against cancer.
Figure: Personalized strategy to identify neoantigen specific lymphocytes in peripheral blood of cancer patients. (i) Peripheral blood mononuclear cells (PBMC) and a tumor biopsy (fresh or archived) are obtained. (iia) PD-1+ lymphocytes are sorted from the peripheral blood and expanded ex vivo. (iib) We extract DNA and RNA from the tumor biopsy and perform exome and RNA sequencing to identify non-synonymous somatic mutations. Tandem minigene (TMG) constructs encoding all the putative mutated 25mers are used as templates to generate in vitro transcribed (IVT) RNA. (iii) IVT TMG RNA is used to transfect autologous antigen presenting cells (APCs) used as targets in a co-culture with the ex vivo expanded lymphocyte subsets. At 20h, T-cell reactivity is analyzed. (Gros, A. et al. Nat Med, 2016).
Junior Principal Investigator
Leticia De Mattos-Arruda
Established this year, VHIO's Applied Genetics of Metastatic Cancer Group, led by Junior Principal Investigator, Leticia De Mattos-Arruda, leads research using integrated multi-omics data to better understand genetic heterogeneity and the role of the immune system within and between tumors for the identification of new biomarkers to guide patient therapy.
With grounded expertise in applying high-throughput molecular approaches to breast cancer, including cutting-edge massively parallel sequencing methods, her group uses liquid biopsies to more effectively track disease and render targeted therapies more precise.
Currently setting up a multidisciplinary and collaborative effort between VHIO researchers, breast cancer clinicians, pathologists, and bioinformaticians to apply genomics, transcriptomics, in silico bioinformatics and histopathologic assessment of tumors, her team will provide further insights into tumor genomic heterogeneity and the role of the microenvironment within and between tumors. The group also aims to discover biomarkers that can be subsequently deployed for monitoring response to therapy and the early detection of disease progression.
Her group has extensive collaborations with leading international investigators in cancer genomics, immuno-oncology and molecular pathology.
Figure: Characterisation of metastasis in the context of precision oncology.
Figure: Leticia De Mattos-Arruda receiving a 2017 ESMO Leaders Generation Program Award, presented by Fortunato Ciardiello, now ESMO Past President (2018-2019).
Laura Pascual Reguant
Gemma Serra Bardenys
Jessica Querol Paños
Our group mainly focuses on the characterization of chromatin dynamics and epigenetics in cancer and epithelial-to-mesenchymal transition (EMT). We hypothesize that during tumor progression and acquisition of malignant traits, global epigenetic changes and high-order chromatin reorganization conspire to convert non-invasive cells with the same DNA sequence into more malignant and aggressive ones. Since these cells behave completely differently within the same biological environment, large-scale mapping of genome-related parameters and their subsequent comparison are necessary to better explore genomes towards advancing our understanding as to how they are transformed into malignant cells.
We aim to use highly-established EMT cellular in vitro models and patient–derived xenografts (PDXs) in different tumor stages (low to high metastatic states) to fully characterize the necessary epigenetic alterations and high-order chromatin reorganization implicated in this process.
Dedicated to fully exploiting these insights into the epigenetic landscape and 3D structure during this malignant transformation, we will adopt chromosome conformation–based techniques together with ChIP-seq, ATAC-seq and RNA-seq. By combining these data with excellent computational and statistical tools during EMT, we will better navigate this largely uncharted area which promises tremendous potential in early diagnosis.
We also aim to describe the association of chromatin conformation changes with the acquisition of malignant traits and evaluate the functional consequences of these developments in genes and pathways. The next step will involve deciphering how these alterations occur at molecular level to more precisely identify these putative culprits for future targeted therapy.
Finally, we will design a multi-genome PCR set of primes and FISH detection paired with a complete bioinformatics analysis platform, with the ultimate aim of translating our research into benefits for patients at clinical level.
Figure: Chromatin organization in the mammalian nucleus. (a) Chromosomes are organized in chromosome territories. (b) Chromosome territories are comprised of fractal globules, and fractal globules from adjacent chromosome territories can interdigitate. (c) Chromatin fibers interact (i) within a fractal globule (frequent), (ii) between fractal globules of the same chromosome territory (rare), or (iii) between adjacent chromosome territories (very rare). (d) Chromatin may form a 30 nm fiber with a solenoid zigzag, or polymer melt organization (see text). (e) Chromatin is resolved as a 10 nm ‘beads on a string’ fiber consisting of nucleosomes.
We aim to describe the epigenetic mechanisms controlling the expression of eukaryotic genes during tumor progression. Our group is particularly interested in the role of the primary structure of chromatin fiber, as determined by histone tail modification, and the 3D chromatin structure implicated in the regulation of transcription.
Mazzolini R, Gonzalez N, Garcia-Garijo A, Millanes-Romero A, Peiró S, Smith S, Garcia de Herreros A and Canudas S. Snail1 transcription factor controls telomere transcription and integrity. Nucleic Acids Res. 2017 Oct 20.
Izquierdo-Bouldstridge A, Bustillos A, Bonet-Costa C, Aribau-Miralbés P, l García-Gomis D, Dabad M, Esteve-Codina A, Pascual-Reguant L, Peiró S, Esteller M, Murtha M, Millán-Ariño L, Jordan A. Histone H1 depletion triggers an interferon response in cancer cells via activation of heterochromatic repeats. Nucleic Acids Res. 2017 Nov 16;45(20):11622-11642.
Verde G, Querol-Paños J, Cebrià-Costa JP, Pascual-Regu ant L, Serra-Bardenys G, Iturbide A and Peiró S. Lysine-Specific Histone Demethylases Contribute to Cellular Differentiation and Carcinogenesis. Epigenomes. 2017, 1(1), 4.
Over the last decade, we have witnessed a true revolution in the treatment of metastatic castration-resistant prostate cancer (mCRPC; the advanced and lethal form of prostate cancer). An improved understanding of its underlying biology has led to the successful development of compounds targeting the androgen signaling pathway, immune system as well as taxanes and radiopharmaceuticals.
Despite the progress in the management of mCRPC, it remains a fatal condition, causing significant morbidity and mortality worldwide. Arguably, the most critical need now in drug development for CRPC is molecular treatment stratification, with the development of drugs in parallel with predictive biomarkers of response. Moreover, the introduction of these novel therapies has driven tumor evolution towards a change in the genomic landscape observed in patients with advanced disease.
Our group aims to serve patients with mCRPC by developing tools towards delivering more individualized patient care based on predictive biomarkers of response and prioritizing the most beneficial anti-cancer medicines and avoiding inefficient treatments for each patient. We will pursue this goal by integrating drug development and clinical trials with correlative biomarker studies from tumor tissue and circulating biomarkers in our laboratory.
Defects in DNA repair genes, particularly in double-strand breaks, are present in 20-25% of mCRPC cases, and will serve as the model to study how we can deliver more precise patient care. We will research how one same gene defect has a functional impact on tumor evolution which can be modulated by the presence of secondary events. Our group will also study the impact of this functional modulation in drug sensitivity assays, focusing on DNA damaging drugs and DNA repair inhibitors to generate hypotheses on optimal patient stratification strategies for clinical trials. We will also study how the use of these drugs can be best combined with therapies targeting androgen signalling.
In order to translate our research into clinical practice, we are setting up the necessary pathways for the systematic collection of tumor metastatic samples - primarily from lesions infiltrating bones - from patients with metastatic prostate cancer treated at Vall d'Hebron, in parallel with blood samples for the study of circulating tumor material.
Figure: Studying prostate cancer genomic evolution in response to treatment-induced pressure. Whole-exome sequencing of circulating cfDNA from a prostate cancer patient receiving a PARP inhibitor treatment identifies polyclonal evolution, in parallel to the disease relapse in some of the original locations in the pelvis (adapted from Goodall, Mateo, Yuan et al; Cancer Discov. 2017).
Mateo J, Ganji G, Lemech C, Burris H A, Han S W, Swales K, et al. A First-Time-in-Human Study of GSK2636771, a Phosphoinositide 3 Kinase Beta-Selective Inhibitor, in Patients with Advanced Solid Tumors. Clin Cancer Res. 2017 Oct 1;23(19):5981-5992
Goodall J, Mateo J, Yuan W, Mossop H, Porta N, Miranda S, et al. (2017). Circulating Cell-Free DNA to Guide Prostate Cancer Treatment with PARP Inhibition. Cancer Discov. 2017 Sep;7(9):1006-1017.
Seed G, Yuan W, Mateo J, Carreira S, Bertan C, Lambros M, Boysen G, Ferraldeschi R, Miranda S, Figueiredo I, Riisnaes R, Crespo M, Rodrigues DN, Talevich E, Robinson DR, Kunju LP, Wu YM, Lonigro R, Sandhu S, Chinnayan A, de Bono JS. Gene Copy Number Estimation From Targeted Next Generation Sequencing Of Prostate Cancer Biopsies: Analytic Validation and Clinical Qualification. Clin Cancer Res. 2017 Oct 15;23(20):6070-6077.
The Radiomics Group was set up at VHIO in October 2017. Since then we have acquired the necessary devices to review medical images and perform post-processing imaging analysis. Two workstations with 4MP display systems, DICOM viewers and imaging analysis software with segmenting tools are available for our group's exclusive use.
We have established collaborations with leading imaging research groups such as the Computing Vision Centre (CVC, Barcelona) and the biomedical research company for imaging biomarkers development, QUIBIM S.L (Valencia). In partnership, we have designed different projects for which we have applied for funding through international grants. We will first initiate an imaging study with functional and anatomical MRI sequences for patients treated with immunotherapy to further establish VHIO as a leading cancer research center in the development of immunotherapeutics. Our goal is to develop and validate novel predictive and response biomarkers for immunotherapy.
We have also established interdisciplinary collaborations with various VHIO groups to work together on several translational research projects. This team science approach is key to optimizing imaging and accelerating translational cancer discovery.
Our group will soon incorporate a postdoc MR researcher to provide support towards advancing novel imaging biomarker development in oncology. We are also pleased to soon welcome our first MSc student and clinical research fellow, and are currently recruiting other new talents to join us.
Aimed at applying imaging biomarkers and radiomics to cancer science, our efforts center on advancing precision imaging in personalized medicine towards ultimately improving outcomes for cancer patients.
Figure: Integrating radiomics in translational research to advance precision medicine in oncology.
Perez-Lopez R, Roda D, Jimenez B, Brown J, Mateo J, Carreira S, Lopez J, Banerji U, Molife R, Koh DM, Kaye S, de Bono J, Tunariu N and Yap T. High Frequency of Radiological Differential Responses with Poly (ADP-ribose) Polymerase Inhibitor Therapy. Oncotarget. 2017 Nov 6;8(61):104430-104443.
Perez-Lopez R, Nava Rodrigues D, Figueiredo I, Mateo J, Collins D, Koh DM, de Bono J, Tunariu N. Multi-Parametric Magnetic Resonance Imaging of Prostate Cancer Bone Disease: Correlation with Bone Biopsy Histological and Molecular Features. Invest Radiol. 2017 Sep 12.
Perez-Lopez R, Mateo J, Mossop H, Blackledge MD, Collins DJ, Rata M, Morgan VA, Macdonald A, Sandhu S, Lorente D, Rescigno P, Zafeiriou Z, Bianchini D, Porta N, Hall E, Leach MO, de Bono JS, Koh DM, Tunariu N. Diffusion-weighted Imaging as a Treatment Response Biomarker Evaluating Bone Metastases in Prostate Cancer: A Pilot Study. Radiology. 2017 Apr; 283(1):168-177.