Programs & Groups

Please click on the corresponding programs below

Recently Incorporated VHIO Groups

Please click on the corresponding groups below

Cellular Plasticity & Cancer
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María Abad
Principal Investigator
Experimental Hematology
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Francesc Bosch
Principal Investigator
Tumor Immunology & Immunotherapy
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Alena Gros
Principal Investigator

New to VHIO in 2017

Applied Genetics of Metastatic Cancer Group
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Leticia De Mattos-Arruda
Junior Principal Investigator
Chromatin Dynamics in Cancer Group
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Sandra Peiró
Principal Investigator
Prostate Cancer Translational Research Group
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Joaquin Mateo
Principal Investigator
Radiomics Group
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Raquel Perez-Lopez
Principal Investigator

Cellular Plasticity & Cancer Group

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Principal Investigator
María Abad

Post-Doctoral Fellow
Elena Senís

Graduate Students
Olga Boix
Emanuela Greco
Iñaki Merino

Student
Noé Crespo

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 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.

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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.

STRATEGIC GOALS

  • Decipher the molecular mechanisms governing the acquisition of stem cell properties during tumorigenesis.
  • Identify and characterize novel micropeptides involved in cancer cell plasticity.
  • Determine the impact of inducing cellular dedifferentiation in various stages of tumorigenesis (tumor initiation, maintenance, and metastasis), and in the resistance of cancer cells to chemotherapeutic agents.
  • Develop new anti-cancer therapies based on the inhibition of cancer cell plasticity.

HIGHLIGHTS

  • Our group received a grant from the Spanish Association for Cancer Research (AECC) to identify novel cancer-related micropeptides.
  • Maria Abad was awarded with the XII FERO Fellowship.
  • We have identified three new micropeptides with tumor suppressor activities, and 5 lncRNA-coded micropeptides that are potentially involved in cancer stemness.

PI PAPER PICK (full list for 2017 below)

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.

HORIZONS 2018

  • Characterize the function of our micropeptides candidates in vivo.
  • Combine bioinformatics and proteomics to identify novel micropeptides implicated in cancer development.
  • Investigate the role of tumor microenvironment in cancer cell dedifferentiation in PDAC models and pancreatic cancer patients’ samples.

PUBLICATIONS

  1. Abad M*, Hashimoto H, Zhou H, Morales MG, Chen B, Bassel-Duby R, and Olson EN*. Notch inhibition enhances cardiac reprogramming by increasing MEF2c transcriptional activity. Stem Cell Reports. 2017 Mar 14;8(3):548-560. * Co-corresponding author.
  2. Marión RM, Lopez-de Silanes I, Mosteiro L, Gamache B, Abad M, Guerra C, Megías D, Serrano M, and Blasco MA. Common telomere changes during in vivo reprogramming and early stages of tumorigenesis. Stem Cell Reports. 2017 Feb 14;8(2):460-475.
  3. Gómez-Cabello D, Checa-Rodriguez C, Abad M, Serrano M and 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.

PROJECTS

  • Programa Estatal de I+D+i Orientada a los Retos de la Sociedad (Governmental Program of R&D oriented to Societal Challenges).
    Ref. number: SAF2015-69413-R
    Principal investigator: Maria Abad
    Funding agency: Spanish Ministry of Economy and Competitiveness (MINECO)
  • Ramón y Cajal Grant
    Ref. number: RYC-2013-14747
    Principal investigator: Maria Abad
    Funding agency: Spanish Ministry of Economy and Competitiveness (MINECO)
  • XII Fero Fellowship
    Principal investigator: Maria Abad
    Funding agency: Fero Foundation
  • AECC Barcelona Provincial Council Projects
    Principal investigator: Maria Abad
    Funding agency: AECC

AWARDS

  • XII Fero Fellowship
    Principal investigator: Maria Abad
    Funding agency: Fero Foundation
  • AECC Barcelona Provincial Council Projects
    Principal investigator: Maria Abad
    Funding agency: AECC
  • AECC postodoctoral fellowship to Elena Senís, PhD
    Principal investigator: Maria Abad
    Funding agency: AECC

Experimental Hematology Group

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Principal Investigator
Francesc Bosch

Translational Research Coordinator
Marta Crespo

Clinical Research Coordinator
Pau Abrisqueta

Phd Students
Sabela Bobillo
Júlia Carabia
Cecilia Carpio
Isabel Jiménez
Júlia Montoro
Guillermo Orti

Post-Doctoral Scientists
Juan Camilo Nieto
Bárbara Tazón

Technician
Lluis Puigdefàbregas

Hematologists/Lab specialists
Pere Barba
Adoración Blanco
Laura Gallur
Merche Gironella
Andrés López
Ana Marín
Bryan Merchan
Pavel Olivera
Margartia Ortega
Carlos Palacio
Verónica Pons
Gaël Roué
Olga Salamero
Amparo Santamaría
David Valcárcel

SUMMARY

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.

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Figure: Interaction between chronic lymphocytic leukemia cells and the tumoral immune microenvironment.

STRATEGIC GOALS

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:

  • Deciphering the mechanisms involved in pathogenesis and progression of hematological neoplasias.
  • The preclinical study of new therapeutic regimens in experimental models that mimic the tumoral microenvironment using primary cells and PDXs.
  • Defining new biomarkers for a more rational and precise treatment of patients.

HIGHLIGHTS

  • We have studied a novel SYK protein inhibitor using our preclinical model of CLL, which has fueled the transition of the drug into the clinic (Purroy et al, Oncotarget. 2016).
  • In an ortothopic mouse model we have shown that XPO-1 inhibition is effective in CNS lymphomas. We are currently designing a clinical trial for these patients.
  • We have defined how an immunosuppressive scenario is related to clinical progression in CLL.
  • Leading the work package dedicated to CLL, our group is a member of the European Innovative Medicines Initiative 2 (MI2) Programme's HARMONY Consortium which focuses on all hematological diseases.

PI PAPER PICK (full list for 2017 below)

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.

HORIZONS 2018

  • To decipher the role of the immune suppression in CLL progression.
  • Define novel therapeutic strategies for patients with CNS lymphoma and apply to the clinic.
  • We will aim to identify new biomarkers of clinical response to stem cell transplantation.
  • Establish a Nanostring platform for determining prognosis in CLL.

PUBLICATIONS

  1. New Molecular Assay for the Proliferation Signature in Mantle Cell Lymphoma Applicable to Formalin-Fixed Paraffin-Embedded Biopsies. 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. 2017.J Clin Oncol.35: 1668-1677.
  2. Obinutuzumab or Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Previously Untreated Diffuse Large B-Cell Lymphoma. Vitolo U; Trnený 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. 2017.J Clin Oncol.35: 3529-3537.
  3. Observation as the initial management strategy in patients with mantle cell lymphoma. Abrisqueta P; Scott DW; Slack GW; Steidl C; Mottok A; Gascoyne RD; Connors JM; Sehn LH; Savage KJ; Gerrie AS; Villa D. 2017.Ann Oncol.28: 2489-2495.
  4. A phase 1b/2b multicenter study of oral panobinostat plus azacitidine in adults with MDS, CMML or AML with ⩽30% blasts.Garcia-Manero G; Sekeres MA; Egyed M; Breccia M; Graux C; Cavenagh JD; Salman H; Illes A; Fenaux P; DeAngelo DJ; Stauder R; Yee K; Zhu N; Lee JH; Valcarcel D; MacWhannell A; Borbenyi Z; Gazi L; Acharyya S; Ide S; Marker M; Ottmann OG. 2017.Leukemia.31: 2799-2806.
  5. Risk of thrombosis according to need of phlebotomies in patients with polycythemia vera treated with hydroxyurea. Alvarez-Larrán A; Pérez-Encinas M; Ferrer-Marín F; Hernández-Boluda JC; Ramírez MJ; Martínez-López J; Magro E; Cruz Y; Mata MI; Aragües P; Fox ML; Cuevas B; Montesdeoca S; Hernández-Rivas JA; García-Gutiérrez V; Gómez-Casares MT; Steegmann JL; Durán MA; Gómez M; Kerguelen A; Bárez A; García MC; Boqué C; Raya JM; Martínez C; Albors M; García F; Burgaleta C; Besses C; Grupo Español de Neoplasias Mieloproliferativas Filadelfia Negativas. 2017.HAEMATOLOGICA.102: 103-109.
  6. The BET bromodomain inhibitor CPI203 improves lenalidomide and dexamethasone activity in in vitro and in vivo models of multiple myeloma by blockade of Ikaros and MYC signaling. Díaz T; Rodríguez V; Lozano E; Mena MP; Calderón M; Rosiñol L; Martínez A; Tovar N; Pérez-Galán P; Bladé J; Roué G; de Larrea CF. 2017.HAEMATOLOGICA.102: 1776-1784.
  7. The Bruton tyrosine kinase inhibitor CC-292 shows activity in mantle cell lymphoma and synergizes with lenalidomide and NIK inhibitors depending on nuclear factor-κBmutational status. Vidal-Crespo A; Rodriguez V; Matas-Cespedes A; Lee E; Rivas-Delgado A; Giné E; Navarro A; Beà S; Campo E; López-Guillermo A; Lopez-Guerra M; Roué G; Colomer D; Pérez-Galán P. 2017.HAEMATOLOGICA.
  8. Lenalidomide maintenance after first-line therapy for high-risk chronic lymphocytic leukaemia (CLLM1): final results from a randomised, double-blind, phase 3 study. Fink AM; Bahlo J; Robrecht S; Al-Sawaf O; Aldaoud A; Hebart H; Jentsch-Ullrich K; Dörfel S; Fischer K; Wendtner CM; Nösslinger T; Ghia P; Bosch F; Kater AP; Döhner H; Kneba M; Kreuzer KA; Tausch E; Stilgenbauer S; Ritgen M; Böttcher S; Eichhorst B; Hallek M. 2017.LANCET HAEMATOL.4: 475-486.
  9. Optimisation of empirical antimicrobial therapy in patients with haematological malignancies and febrile neutropenia (How Long study): an open-label, randomised, controlled phase 4 trial. Aguilar-Guisado M; Espigado I; Martín-Peña A; Gudiol C; Royo-Cebrecos C; Falantes J; Vázquez-López L; Montero MI; Rosso-Fernández C; de la Luz Martino M; Parody R; González-Campos J; Garzón-López S; Calderón-Cabrera C; Barba P; Rodríguez N; Rovira M; Montero-Mateos E; Carratalá J; Pérez-Simón JA; Cisneros JM. 2017.LANCET HAEMATOL.
  10. Excess mortality in the myelodysplastic syndromes.Nomdedeu M; Pereira A; Ramos F; Valcárcel D; Costa D; Arnan M; Calvo X; Pomares H; Luño E; Díaz-Campelo M; Collado R; de Paz R; Falantes JF; Pedro C; Marco J; Oirtzabal I; Sánchez-García J; Tormo M; Cedena MT; Nomdedeu B; Sanz G; Spanish MDS Group. 2017.AM J HEMATOL.92: 149-154.
  11. Enumerating bone marrow blasts from nonerythroid cellularity improves outcome prediction in myelodysplastic syndromes and permits a better definition of the intermediate risk category of the Revised International Prognostic Scoring System (IPSS-R). Calvo X; Arenillas L; Luño E; Senent L; Arnan M; Ramos F; Pedro C; Tormo M; Montoro J; Díez-Campelo M; Blanco ML; Arrizabalaga B; Xicoy B; Bonanad S; Jerez A; Nomdedeu M; Ferrer A; Sanz GF; Florensa L. 2017.AM J HEMATOL.92: 614-621.
  12. Inhibition of BCR signaling using the Syk inhibitor TAK-659 prevents stroma-mediated signaling in chronic lymphocytic leukemia cells. Purroy N; Carabia J; Abrisqueta P; Egia L; Aguiló M; Carpio C; Palacio C; Crespo M; Bosch F. 2017.Oncotarget.8: 742-756.
  13. Patients with chronic lymphocytic leukemia and complex karyotype show an adverse outcome even in absence of TP53/ATM FISH deletions. Puiggros, Anna; Collado, Rosa; Jose Calasanz, Maria; Ortega, Margarita; Ruiz-Xiville, Neus; Rivas-Delgado, Alfredo; Luno, Elisa; Gonzalez, Teresa; Navarro, Blanca; Garcia-Malo, MaDolores; Valiente, Alberto; Angel Hernandez, Jose; Teresa Ardanaz, Maria; Angeles Pinan, Maria; Laura Blanco, Maria; Hernandez-Sanchez, Maria; Batlle-Lopez, Ana; Salgado, Rocio; Salido, Marta; Ferrer, Ana; Abrisqueta, Pau; Gimeno, Eva; Abella, Eugenia; Ferra, Christelle; Jose Terol, Maria; Ortuno, Francisco; Costa, Dolors; Moreno, Carol; Carbonell, Felix; Bosch, Francesc; Delgado, Julio; Espinet, Blanca. 2017.Oncotarget.8: 54297-54303.
  14. Hematopoietic Cell Transplantation Comorbidity Index Predicts Outcomes in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndromes Receiving CD34(+) Selected Grafts for Allogeneic Hematopoietic Cell Transplantation. Barba P; Ratan R; Cho C; Ceberio I; Hilden P; Devlin SM; Maloy MA; Barker JN; Castro-Malaspina H; Jakubowski AA; Koehne G; Papadopoulos EB; Ponce DM; Sauter C; Tamari R; van den Brink MR; Young JW; O'Reilly RJ; Giralt SA; Perales MA. 2017.Biol Blood Marrow Transplant.23: 67-74.
  15. Ex Vivo CD34(+)-Selected T Cell-Depleted Peripheral Blood Stem Cell Grafts for Allogeneic Hematopoietic Stem Cell Transplantation in Acute Leukemia and Myelodysplastic. Syndrome Is Associated with Low Incidence of Acute and Chronic Graft-versus-Host Disease and High Treatment Response. Barba P; Hilden P; Devlin SM; Maloy M; Dierov D; Nieves J; Garrett MD; Sogani J; Cho C; Barker JN; Kernan NA; Castro-Malaspina H; Jakubowski AA; Koehne G; Papadopoulos EB; Prockop S; Sauter C; Tamari R; van den Brink MR; Avecilla ST; Meagher R; O'Reilly RJ; Goldberg JD; Young JW; Giralt S; Perales MA; Ponce DM. 2017.Biol Blood Marrow Transplant.23: 452-458.
  16. Early and Long-Term Impaired T Lymphocyte Immune Reconstitution after Cord Blood Transplantation with Antithymocyte Globulin. Castillo N; García-Cadenas I; Barba P; Canals C; Díaz-Heredia C; Martino R; Ferrà C; Badell I; Elorza I; Sierra J; Valcárcel D; Querol S. 2017.Biol Blood Marrow Transplant.23: 491-497.
  17. Do Patients and Physicians Agree When They Assess Quality of Life? Barata A; Martino R; Gich I; García-Cadenas I; Abella E; Barba P; Briones J; Brunet S; Esquirol A; García-Pallarols F; Garrido A; Granell M; Martinez J; Mensa I; Novelli S; Sanchez-Blanco B; Valcárcel D; Sierra J. 2017.Biol Blood Marrow Transplant.23: 1005-1010.
  18. Outcomes after Umbilical Cord Blood Transplantation for Myelodysplastic Syndromes. Gerds AT; Woo Ahn K; Hu ZH; Abdel-Azim H; Akpek G; Aljurf M; Ballen KK; Beitinjaneh A; Bacher U; Cahn JY; Chhabra S; Cutler C; Daly A; DeFilipp Z; Gale RP; Gergis U; Grunwald MR; Hale GA; Hamilton BK; Jagasia M; Kamble RT; Kindwall-Keller T; Nishihori T; Olsson RF; Ramanathan M; Saad AA; Solh M; Ustun C; Valcárcel D; Warlick E; Wirk BM; Kalaycio M; Alyea E; Popat U; Sobecks R; Saber W. 2017.Biol Blood Marrow Transplant.23: 971-979.
  19. A Time-to-Event Model for Acute Kidney Injury after Reduced-Intensity Conditioning Stem Cell Transplantation Using a Tacrolimus- and Sirolimus-based Graft-versus-Host Disease Prophylaxis. Piñana JL; Perez-Pitarch A; Garcia-Cadenas I; Barba P; Hernandez-Boluda JC; Esquirol A; Fox ML; Terol MJ; Queraltó JM; Vima J; Valcarcel D; Ferriols-Lisart R; Sierra J; Solano C; Martino R. 2017.Biol Blood Marrow Transplant.23: 1177-1185.
  20. Autologous Stem Cell Transplantation for Follicular Lymphoma: Favorable Long-Term Survival Irrespective of Pretransplantation Rituximab Exposure. Jiménez-Ubieto A; Grande C; Caballero D; Yáñez L; Novelli S; Hernández-Garcia MT; Manzanares M; Arranz R; Ferreiro JJ; Bobillo S; Mercadal S; Galeo A; López Jiménez J; Moraleda JM; Vallejo C; Albo C; Pérez E; Marrero C; Magnano L; Palomera L; Jarque I; Martínez-Sánchez P; Martín A; Coria E; López-Guillermo A; Salar A; Lahuerta JJ. 2017.Biol Blood Marrow Transplant.23: 1631-1640.
  21. Efficacy of ß-Lactam/ß-Lactamase Inhibitor Combinations for the Treatment of Bloodstream Infection Due to Extended-Spectrum-ß-Lactamase-Producing Enterobacteriaceae in Hematological Patients with Neutropenia. Gudiol C; Royo-Cebrecos C; Abdala E; Akova M; Álvarez R; Maestro-de la Calle G; Cano A; Cervera C; Clemente WT; Martín-Dávila P; Freifeld A; Gómez L; Gottlieb T; Gurguí M; Herrera F; Manzur A; Maschmeyer G; Meije Y; Montejo M; Peghin M; Rodríguez-Baño J; Ruiz-Camps I; Sukiennik TC; Tebe C; Carratalà J; BICAR Study Group. 2017.Antimicrob Agents Chemother.
  22. Microenvironment regulates the expression of miR-21 and tumor suppressor genes PTEN, PIAS3 and PDCD4 through ZAP-70 in chronic lymphocytic leukemia. Carabia J; Carpio C; Abrisqueta P; Jiménez I; Purroy N; Calpe E; Palacio C; Bosch F; Crespo M. 2017.Sci Rep.7: 12262-0.
  23. Cytoplasmic cyclin D1 controls the migration and invasiveness of mantle lymphoma cells. Body S; Esteve-Arenys A; Miloudi H; Recasens-Zorzo C; Tchakarska G; Moros A; Bustany S; Vidal-Crespo A; Rodriguez V; Lavigne R; Com E; Casanova I; Mangues R; Weigert O; Sanjuan-Pla A; Menéndez P; Marcq B; Picquenot JM; Pérez-Galán P; Jardin F; Roué G; Sola B. 2017.Sci Rep.7: 13946-0.
  24. Patterns of infection and infection-related mortality in patients with steroid-refractory acute graft versus host disease. García-Cadenas I; Rivera I; Martino R; Esquirol A; Barba P; Novelli S; Orti G; Briones J; Brunet S; Valcarcel D; Sierra J. 2017.Bone Marrow Transplant.52: 107-113.
  25. Tacrolimus plus sirolimus with or without ATG as GVHD prophylaxis in HLA-mismatched unrelated donor allogeneic stem cell transplantation. Kharfan-Dabaja MA; Parody R; Perkins J; Lopez-Godino O; Lopez-Corral L; Vazquez L; Caballero D; Falantes J; Shapiro J; Ortí G; Barba P; Valcárcel D; Esquirol A; Martino R; Piñana JL; Solano C; Tsalatsanis A; Pidala J; Anasetti C; Perez-Simón JA. 2017.Bone Marrow Transplant.52: 438-444.
  26. Long-term prognosis for 1-year relapse-free survivors of CD34+ cell-selected allogeneic hematopoietic stem cell transplantation: a landmark analysis. Cho C; Hsu M; Barba P; Maloy MA; Avecilla ST; Barker JN; Castro-Malaspina H; Giralt SA; Jakubowski AA; Koehne G; Meagher RC; O'Reilly RJ; Papadopoulos EB; Ponce DM; Tamari R; van den Brink MRM; Young JW; Devlin SM; Perales MA. 2017.Bone Marrow Transplant.52: 1629-1636.
  27. An analysis of the kinetics of molecular response during the first trimester of treatment with nilotinib in newly diagnosed chronic myeloid leukemia patients in chronic phase..Steegmann JL; Colomer D; Gómez-Casares MT; García-Gutiérrez V; Ortí G; Ramírez-Payer A; Olavarria E; Vall-Llovera F; Giraldo P; Conde E; Vallansot R; López-Lorenzo JL; Palomera L; Álvarez-Larrán A; Conesa V; Bautista G; Casas L; Giles F; Hochhaus A; Casado-Montero LF. 2017.J Cancer Res Clin Oncol.143: 2059-2066.
  28. Progression-free survival at 2 years post-autologous transplant: a surrogate end point for overall survival in follicular lymphoma. Jiménez-Ubieto A; Grande C; Caballero D; Yáñez L; Novelli S; Hernández MT; Manzanares M; Arranz R; Ferreiro JJ; Bobillo S; Mercadal S; Galego A; Jiménez JL; Moraleda JM; Vallejo C; Albo C; Pérez E; Marrero C; Magnano L; Palomera L; Jarque I; Coria E; Rodriguez A; Martín A; López-Guillermo A; Salar A; Lahuerta JJ; GELTAMO (Grupo Español de Linfomas y Trasplantes de Médula Ósea) cooperative stu. 2017.Cancer Med.6: 2766-2774.
  29. Calreticulin mutations are exceedingly rare in patients with myelodysplastic syndromes with myelofibrosis. Montoro J; Robledo C; Zamora L; Valcárcel D; Ramos F. 2017.ANN HEMATOL.96: 317-318.
  30. Cytomorphology review of 100 newly diagnosed lower-risk MDS patients in the European LeukemiaNet MDS (EUMDS) registry reveals a high inter-observer concordance. de Swart L; Smith A; MacKenzie M; Symeonidis A; Neukirchen J; Mikulenková D; Vallespí T; Zini G; Paszkowska-Kowalewska M; Kruger A; Saft L; Fenaux P; Bowen D; Hellström-Lindberg E; Cermák J; Stauder R; Tatic A; Holm MS; Malcovati L; Madry K; Droste J; Blijlevens N; de Witte T; Germing U. 2017.ANN HEMATOL.96: 1105-1112.
  31. Clinical characteristics of patients with central nervous system relapse in BCR-ABL1-positive acute lymphoblastic leukemia: the importance of characterizing ABL1 mutations in cerebrospinal fluid. Sanchez R; Ayala R; Alonso RA; Martínez MP; Ribera J; García O; Sanchez-Pina J; Mercadal S; Montesinos P; Martino R; Barba P; González-Campos J; Barrios M; Lavilla E; Gil C; Bernal T; Escoda L; Abella E; Amigo ML; Moreno MJ; Bravo P; Guàrdia R; Hernández-Rivas JM; García-Guiñón A; Piernas S; Ribera JM; Martínez-López J. 2017.ANN HEMATOL.96: 1069-1075.
  32. Prophylaxis with enoxaparin for prevention of venous thromboembolism after lung transplantation: a retrospective study. Sáez-Giménez B; Berastegui C; Sintes H; Perez-Miranda J; Figueredo A; López Meseguer M; Monforte V; Bravo C; Santamaría A; Ramon MA; Gómez-Ollés S; Roman A. 2017.TRANSPL INT.30: 1266-1274.
  33. Further psychometric validation of the GAH scale: Responsiveness and effect size. Cruz-Jentoft AJ; González B; de la Rubia J; Hernández Rivas JÁ; Soler JA; Fernández Lago C; Arnao M; Gironella M; Pérez Persona E; Zudaire MT; Olivier C; Altés A; García Guiñón A; Nomdedeu B; Arnan M; Ramírez Payer Á; Sánchez-Godoy P; Pajuelo N; Vilanova D; Monjil DF; Bonanad S; GAH Group. 2017.J GERIATR ONCOL.8: 211-215.
  34. Donor lymphocyte infusions in AML and MDS: Enhancing the graft-versus-leukemia effect. Orti G; Barba P; Fox L; Salamero O; Bosch F; Valcarcel D. 2017.EXP HEMATOL.48: 1-11.
  35. Frequency and prognostic significance of t(v;11q23)/KMT2A rearrangements in adult patients with acute lymphoblastic leukemia treated with risk-adapted protocols. Motlló C; Ribera JM; Morgades M; Granada I; Montesinos P; Brunet S; Bergua J; Tormo M; García-Boyero R; Sarrà J; Del Potro E; Grande C; Barba P; Bernal T; Amigo ML; Grau J; Cervera J; Feliu E; PETHEMA Group, Spanish Society of Hematology. 2017.Leuk Lymphoma.58: 145-152.
  36. Predictive factors for anemia response to erythropoiesis-stimulating agents in myelofibrosis. Hernández-Boluda JC; Correa JG; García-Delgado R; Martínez-López J; Alvarez-Larrán A; Fox ML; García-Gutiérrez V; Pérez-Encinas M; Ferrer-Marín F; Mata-Vázquez MI; Raya JM; Estrada N; García S; Kerguelen A; Durán MA; Albors M; Cervantes F. 2017.EUR J HAEMATOL.98: 407-414.
  37. Spuriously low pulse oximetry saturation associated with hemoglobin Sydney in a child and relatives: Identification of this unstable hemoglobin may avoid unnecessary testing and hospital admissions..de Sevilla MF; Català A; Rives S; Berrueco R; Vidiella N; Camós M; Torrebadell M; Alonso-Saladrigues A; Mesegué M; Ruiz-Llobet A; Blanco-Álvarez A; Benéitez D. 2017.PEDIATR BLOOD CANCER.
  38. Clinical and biological significance of isolated Y chromosome loss in myelodysplastic syndromes and chronic myelomonocytic leukemia. A report from the Spanish MDS Group..Nomdedeu M; Pereira A; Calvo X; Colomer J; Sole F; Arias A; Gomez C; Luño E; Cervera J; Arnan M; Pomares H; Ramos F; Oiartzabal I; Espinet B; Pedro C; Arrizabalaga B; Blanco ML; Tormo M; Hernandez-Rivas JM; Díez-Campelo M; Ortega M; Valcárcel D; Cedena MT; Collado R; Grau J; Granada I; Sanz G; Campo E; Esteve J; Costa D; Spanish MDS Group. 2017.Leuk Res.63: 85-89.
  39. Clinical efficacy of ß-lactam/ß-lactamase inhibitor combinations for the treatment of bloodstream infection due to extended-spectrum ß-lactamase-producing Enterobacteriaceae in haematological patients with neutropaenia: a study protocol for a retrospective observational study (BICAR). Gudiol C; Royo-Cebrecos C; Tebe C; Abdala E; Akova M; Álvarez R; Maestro-de la Calle G; Cano A; Cervera C; Clemente WT; Martín-Dávila P; Freifeld A; Gómez L; Gottlieb T; Gurguí M; Herrera F; Manzur A; Maschmeyer G; Meije Y; Montejo M; Peghin M; Rodríguez-Baño J; Ruiz-Camps I; Sukiennik TC; Carratalà J; BICAR study group. 2017.BMJ OPEN.
  40. Consensus guidelines for diagnosis, treatment and follow-up of patients with pancreatic cancer in Spain. Hidalgo M; Álvarez R; Gallego J; Guillén-Ponce C; Laquente B; Macarulla T; Muñoz A; Salgado M; Vera R; Adeva J; Alés I; Arévalo S; Blázquez J; Calsina A; Carmona A; de Madaria E; Díaz R; Díez L; Fernández T; de Paredes BG; Gallardo ME; González I; Hernando O; Jiménez P; López A; López C; López-Ríos F; Martín E; Martínez J; Martínez A; Montans J; Pazo R; Plaza JC; Peiró I; Reina JJ; Sanjuanbenito A; Yaya R; Carrato A. 2017.Clin Transl Oncol.19: 667-681.
  41. Asparaginase use for the treatment of acute lymphoblastic leukemia..Barba P; Dapena JL; Montesinos P; Rives S. 2017.Med Clin (Barc).148: 225-231.
  42. Update of the Grupo Español de Leucemia Linfocítica Crónica clinical guidelines of the management of chronic lymphocytic leukemia. García-Marco JA; Delgado J; Hernández-Rivas JA; Ramírez Payer Á; Loscertales Pueyo J; Jarque I; Abrisqueta P; Giraldo P; Martínez R; Yáñez L; Terol MJ; González M; Bosch F; en nombre del Grupo Español de Leucemia Linfocítica Crónica (GELLC). 2017.Med Clin (Barc).148: 3811-3819.
  43. Bridge therapy in patients under anticoagulation: Is it still the question? Santamaría A. 2017.Med Clin (Barc).149: 303-304.
  44. Analytical parameters and vital signs in patients subjected to dental extraction. Jané-Pallí E; Arranz-Obispo C; González-Navarro B; Murat J; Ayuso-Montero R; Rojas S; Santamaría A; Jané-Salas E; López-López J. 2017.J Clin Exp Dent.
  45. Single umbilical cord blood with or without CD34+ cells from a third-party donor in adults with leukemia. Sanz J; Kwon M; Bautista G; Sanz MA; Balsalobre P; Piñana JL; Solano C; Duarte R; Ferrá C; Lorenzo I; Martín C; Barba P; Pascual MJ; Martino R; Gayoso J; Buño I; Regidor C; de la Iglesia A; Montoro J; Díez-Martín JL; Sanz GF; Cabrera R. 2017.Blood Adv.1: 1047-1055.

PROJECTS

  • Leucemia linfática crónica: progresión de la enfermedad y microambiente tumoral
    PI: Francesc Bosch
    Funding Entity: ISCIII
    Duration: 2015 – 2017
  • Patogènesi i noves dianes moleculars en síndromes limfoproliferatives B
    PI: Marta Crespo
    Funding Entity: MINECO
    Duration: 2014 – 2017
  • Targeted therapy for acute myeloid leukemia: ex vivo testing under conditions mimicking the bone marrow microenvironment
    PI: Marta Crespo
    Funding Entity: AECC, Barcelona
    Duration: 2016 – 2017
  • General
    PI: Francesc Bosch Funding Entity: La Generalitat de CatalunyaDuration: 2014 - ongoing

Tumor Immunology & Immunotherapy Group

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Principal Investigator
Alena Gros

Post-Doctoral Fellow
Carlos Alberto Fajardo

Graduate Students
Andrea Garcia
Maria Lozano

Technicians
Daniela Grases
Alejandro Negro

SUMMARY

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.

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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).

STRATEGIC GOALS

  • Characterize personalized anti-tumor T-cell response in patients with cancer.
  • Mine the personalized repertoire of tumor-reactive lymphocytes for potential biomarkers of response to cancer immunotherapy.
  • Investigate novel strategies to rapidly identify tumor-reactive lymphocytes as well as the target antigens driving this response.
  • Develop personalized T-cell-based cancer immunotherapies for patients with solid cancers.

HIGHLIGHTS

  • Alena Gros secured funding for 4 new projects.
  • Our group has collected over 100 samples from patients treated at the Vall d'Hebron University Hospital (HUVH) to study mechanisms of response and resistance to immunotherapy.
  • Alena's group is setting up a collaboration with the Blood and Tissue Bank in Barcelona, to make adoptive cell transfer a clinical reality throughout the region.

HORIZONS 2018

  • Use proteogenomics to identify neoantigen-specific and tumor-reactive cells.
  • Characterize the phenotype of circulating lymphocytes and changes following treatment with immune checkpoint inhibitors.
  • Develop non-invasive personalized T-cell based therapies for patients with solid cancers.

PROJECTS

  • Grantor: Miguel Servet Tipo I.
    Title: Characterization of neoantigen-specific T cells and identification of predictive biomarkers of response in patients with MSI and MSI-like CRC treated with anti-PDL1.
  • Grantor: Insitituto de Salud Carlos III.
    Title:Identificación de antígenos tumorales no canónicos y análisis de su relevancia en la inmunoterapia del cáncer
  • Grantor: Asociación Española Contra el Cáncer (Lab AECC).
    Title:Identification of biomarkers of response to cancer immunotherapy in liquid biopsies.
  • Grantor:Asociación Española Contra el Cáncer (Ideas Semilla).
    Title:Identification of the personalized repertoire of immunogenic tumor rejection epitopes.
  • Grantor: EMD Serono (Grant for Oncology Innovation).
    Title: Personalized non-invasive T-cell therapies targeting the mutanome

Applied Genetics of Metastatic Cancer Group

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Junior Principal Investigator
Leticia De Mattos-Arruda

SUMMARY

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.

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Figure: Characterisation of metastasis in the context of precision oncology.

STRATEGIC GOALS

  • Integrate multi-omics data to better understand genetic heterogeneity and the role of the immune system within and between tumors - longitudinally and in warm autopsy specimens - from patients with metastatic breast cancers.
  • Identify biomarkers to more precisely guide the selection of anti-cancer therapies based on the specificities of individual patients.
  • Optimize the post-mortem studies of metastatic breast cancer patients in collaboration with VHIO's Breast Cancer Group.
  • Use multi-omics to understand differential clinical responses in metastatic breast cancer patients.

HIGHLIGHTS

  • In collaboration with the Cancer Research UK Cambridge Institute (Carlos Caldas' laboratory), we continue to pursue potentially ground-breaking research aimed at characterising tissue location-dependent and independent genome sequence and microenvironmental changes in metastatic breast cancers.
  • Leticia was appointed as ESMO faculty member for breast cancer and also joined the Editorial Board of ESMO Open: Cancer Horizons, the Society's online oncology journal, in the breast cancer field (2018 / 2019).
  • She has frequently been invited as speaker at national international conferences (13th Meet the Professor, Advanced International Breast Cancer Course(AIBCC) – lecture: Liquid biopsy: Circulating tumor DNA (ctDNA), Circulating tumor cells (CTCs): Are they ready for clinical use?, Padua, Italy; 2017 ECCO Congress – lecture: Circulating tumor DNA: Today, Amsterdam, Netherlands, January 2017).
  • Leticia has participated as an ad hoc breast cancer expert member on the Advisory Board of the European Medicines Agency (EMA).

PI PAPER PICK (full list for 2017 below)

  • De Mattos-Arruda L. Liquid biopsy for HER2-positive breast cancer brain metastasis: the role of the cerebro-spinal fluid. ESMO Open. 2017 Oct 9;2(4):e000270.
  • Callari M, Sammut SJ, De Mattos-Arruda L, Bruna A, Rueda OM, Chin SF, Caldas C. Intersect-then-combine approach: improving the performance of somatic variant calling in whole exome sequencing data using multiple aligners and callers. Genome Med. 2017 Apr 18;9(1):35.
  • Ramon YCS, Capdevila C, Hernandez-Losa J, De Mattos-Arruda L, Ghosh A, Lorent J, Larsson O, Aasen T, Postovit L M, Topisirovic I. Cancer as an ecomolecular disease and a neoplastic consortium. Biochim Biophys Acta. 2017 Dec;1868(2):484-499.
  • Banerjee S, Califano R, Corral J, de Azambuja E, De Mattos-Arruda L, Guarneri V, Hutka M, Jordan K, Martinelli E, Mountzios G, Ozturk MA, Petrova M, Postel-Vinay S, Preusser M, Qvortrup C, Volkov MNM, Tabernero J, Olmos D, Strijbos MH. Professional Burnout in European Young Oncologists: Results of The European Society For Medical Oncology (ESMO) Young Oncologists Committee Burnout Survey. Ann Oncol. 2017 Jul 1;28(7):1590-1596.

HORIZONS 2018

  • Establish our cancer mouse models at VHIO to initiate in vivo
  • Functionally characterize the already identified lncRNA-coded micropeptides implicated in cancer stemness.
  • Combine bioinformatics and proteomics to identify novel micropeptides implicated in cancer development, and then validate and characterize them.
  • Generate a collection of patient-derived tumor organoids to analyse the impact of cellular dedifferentiation in vitro.
  • Investigate the role of tumor microenvironment in cancer cell dedifferentiation in PDAC models.

PUBLICATIONS

  1. De Mattos-Arruda L. Liquid biopsy for HER2-positive breast cancer brain metastasis: the role of the cerebro-spinal fluid. ESMO Open. 2017 Oct 9;2(4):e000270.
  2. Callari M, Sammut SJ, De Mattos-Arruda L, Bruna A, Rueda OM, Chin SF, Caldas C. Intersect-then-combine approach: improving the performance of somatic variant calling in whole exome sequencing data using multiple aligners and callers. Genome Med. 2017 Apr 18;9(1):35.
  3. Ramon YCS, Capdevila C, Hernandez-Losa J, De Mattos-Arruda L, Ghosh A, Lorent J, Larsson O, Aasen T, Postovit L M, Topisirovic I. Cancer as an ecomolecular disease and a neoplastic consortium. Biochim Biophys Acta. 2017 Dec;1868(2):484-499.
  4. Banerjee S, Califano R, Corral J, de Azambuja E, De Mattos-Arruda L, Guarneri V, Hutka M, Jordan K, Martinelli E, Mountzios G, Ozturk MA, Petrova M, Postel-Vinay S, Preusser M, Qvortrup C, Volkov MNM, Tabernero J, Olmos D, Strijbos MH. Professional Burnout in European Young Oncologists: Results of The European Society For Medical Oncology (ESMO) Young Oncologists Committee Burnout Survey. Ann Oncol. 2017 Jul 1;28(7):1590-1596.
  5. Aapro M, Astier A, Audisio R, Banks I, Bedossa P, Brain E, Cameron D, Casali P, Chiti A, De Mattos-Arruda L, Kelly D, Lacombe D, Nilsson PJ, Piccart M, Poortmans P, Riklund K, Saeter G, Schrappe M, Soffietti R, Travado L, van Poppel H, Wait S, Naredi P. Identifying critical steps towards improved access to innovation in cancer care: a European CanCer Organisation position paper. Eur J Cancer 2017;82:193-202.

PROJECTS

  • The integrated genomic and immune landscapes of lethal metastatic breast cancer.
  • Genetic heterogeneity and actionable mutations in HER2-positive primary breast cancers and their brain metastases.

AWARDS

  • Leticia De Mattos-Arruda was appointed by the European Society for Medical Oncology(ESMO)as member of its Breast Cancer Faculty Group (2017-2021). The role of this group is to help ESMO deliver on its committed efforts aimed at promoting education across the globe.
  • Leticia was invited to join ESMO Open’s Editorial Board in the breast cancer field (2018-2019).
  • She has also served as an ad hoc expert member in breast cancer for the Advisory Board of the European Medicines Agency (EMA).
  • Leticia was selected and awarded as part of the 2017 ESMO Leaders Generation Program (click here).
  • Collaborative work with Carlos Caldas’ Group, Cancer Research UK (CRUK), in analysing the role of genomics, transcriptomics and the immune system in metastatic breast cancers.
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Figure: Leticia De Mattos-Arruda receiving a 2017 ESMO Leaders Generation Program Award, presented by Fortunato Ciardiello, now ESMO Past President (2018-2019).

Chromatin Dynamics in Cancer Group

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Principal Investigator
Sandra Peiró

Post-Doctoral Fellow
Gaetano Verde

PhD Students
Marc Cosin
Laura Pascual Reguant
Gemma Serra Bardenys

Technician
Jessica Querol Paños

SUMMARY

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.

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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.

STRATEGIC GOALS

    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.

  • Identify the molecular mechanisms of chromatin conformation changes in tumor cells; identify potential druggable proteins.
  • Discover the key enhancer-promoter interactions during acquisition of malignant traits as well as associated transcription factors.
  • The molecular characterization of the LOXL2_BRD4 axis in triple-negative breast cancer (TNBC) cells.

HIGHLIGHTS

  • Sandra Peiró's group joined VHIO in December 2016.
  • We have revealed the role of oxidized histone H3 in chromatin compaction and cell death resistance in triple-negative breast cancer (TNBC).
  • Our group has also evidenced the role of Lamin B1 in chromatin reorganization during epithelial-to-mesenchymal transition (EMT).

PI PAPER PICK (full list for 2017 below)

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.

HORIZONS 2018

  • Data analysis by ATACseq and ChIP seq for the identification of key enhancer-promoter interactions and the transcription factors involved during EMT and in triple-negative breast cancer (TNBC) cells.
  • Molecular characterization of the LOXL2_BRD4 axis in triple-negative breast cancer (TNBC) cells.
  • Generate a collection of patient-derived xenografts from Nut-Midline-Carcinoma patients to understand the role of NUT-BRD proteins in chromatin organization and gene regulation.

PUBLICATIONS

  1. 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.
  2. 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.
  3. 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.

PROJECTS

  • Project title: Finding oxH3 readers
    Funding: Fundació MaratóTV3
    Duration: 2014 – 2017
    Principal Investigator: Sandra Peiró
  • Project title: Chromatin Structure in EMT
    Funding: Instituto de Salud Carlos III (Institute of Health Carlos III, ISCIII)
    Duration: 2016 – 2019
    Principal Investigator: Sandra Peiró
  • Project title: Molecular mechanisms of BET inhibition in Estrogen Receptor-Positive   Breast Cancer Cells Resistant to CDK4/6 Treatment   
    Funding: Zenith Epigenetics (ISCIII)
    Duration: 2017 – 2019
    Principal Investigator: Sandra Peiró

Prostate Cancer Translational Research Group

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Principal Investigator
Joaquin Mateo

SUMMARY

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.

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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).

STRATEGIC GOALS

  • Advance towards a clinically relevant re-classification of metastatic prostate cancer integrating genotypic and phenotypic data with functional assays.
  • Develop prostate cancer molecular stratification assays based on circulating biomarkers.
  • Build a precision medicine core for prostate cancer patients treated at the Vall d'Hebron University Hospital (HUVH).

HIGHLIGHTS

  • Joaquin Mateo joined VHIO in November 2017.
  • By the close of 2017, 3 scientists were recruited and will join the group throughout Q1 2018: Alejandro Athie, for genomics and bioinformatics analysis, Gonzalo Hernández, to work on functional molecular biology assays, and Teresa Casals as lab manager.
  • Our group, together with VHIO's Genitourinary, CNS Tumors, Sarcoma & Cancer of Unknown Primary Site Group, led by Joan Carles (click here), has launched a program to prospectively acquire samples from metastatic lesions and circulating biomarkers from patients with metastatic prostate cancer treated at Vall d'Hebron.

PI PAPER PICK (full list for 2017 below)

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.

HORIZONS 2018

  • Study how AR and TP53 signaling modulate DNA repair proficiency in prostate cancer models.
  • RNA profiling of prostate cancer metastatic samples with and without genomic defects in DNA repair genes.
  • Optimize clinical obtention of bone marrow metastatic samples for the isolation of tumor genomic material towards patient stratification for clinical trials.
  • To set up a pathway to evaluate circulating tumor cells from prostate cancer patients.

PUBLICATIONS

  1. 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. Clinical Cancer Research,2017; 23(19), 5981–5992
  2. 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 Discovery, 7(9), 1006–1017. doi:10.1158/2159-8290.CD-17-0261
  3. Seed, W. Yuan, J. Mateo, S. Carreira, C. Bertan, M. Lambros, G. Boysen, R. Ferraldeschi, S. Miranda, I. Figueiredo, R. Riisnaes, M. Crespo, D. Nava Rodrigues, E. Talevich, D. Robinson, LaL.kshmi Kunju, Y Wu, R. Lonigro, S. Sandhu, A. Chinnayan, J. de Bono. Gene Copy Number Estimation From Targeted Next Generation Sequencing Of Prostate Cancer Biopsies: Analytic Validation and Clinical Qualification. Clinical Cancer Research, 2017;23(20):6070-6077
  4. Mateo J, Boysen G, Barbieri CE, Bryant HE, Castro E, Nelson PS, Olmos D, Pritchard CC, Rubin MA, de Bono JS. DNA repair in prostate cancer: biology and clinical implications. Eur Urol 2017; 71(3):417-425
  5. Massard C, MateoJ, Loriot Y, Pezaro C, Albiges L, Mehra N, Varga A, Bianchini D, Ryan CJ, Petrylak DP, Attard G, Shen L, Fizazi K, de Bono J. : Phase I/II trial of cabazitaxel plus abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel and abiraterone. Annals of Oncology. 2017 Jan 1;28(1):90-95

PROJECTS

  • Grantor: PROSTATE CANCER FOUNDATION, Defining the Landscape and Clinical Relevance of ATM Defects in Lethal Prostate Cancer.
  • Grantor: Fundación SEOM, Caracterización del impacto funcional de mutaciones en genes de la reparación del DNA en pacientes con cáncer de próstata.

AWARDS

  • Beca FSEOM para retorno o intensificación de investigadores
  • ASCO Cancer Conquer Foundation Merit Award

Radiomics Group

Imagen

Principal Investigator
Raquel Perez-Lopez

SUMMARY

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.

Imagen

Figure: Integrating radiomics in translational research to advance precision medicine in oncology.

STRATEGIC GOALS

  • Provide expertise in engineering and bioinformatics for the development and clinical qualification of quantitative imaging biomarkers for precision medicine to improve outcomes for cancer patients.
  • Use functional imaging for optimizing drug development through clinical trials.
  • Integrate radiomics and genomics in translational studies towards a deeper understanding of tumor evolution and mechanisms of resistance to anti-cancer therapies.
  • Optimize and standardize imaging acquisition protocols.
  • Develop and implement computational models for advanced image processing.

HIGHLIGHTS

  • Our Radiomics Group launched at VHIO in October 2017.
  • Research focuses on the development and validation of novel imaging biomarkers in oncology.
  • Multiple collaborations with VHIO groups and other institutions have already been established.
  • We continue to expand existing partnerships with other groups and establish new ones in order to increase the incorporation of imaging studies within translational research projects.
  • We apply imaging biomarkers and radiomics to research in oncology.

PI PAPER PICK (full list for 2017 below)

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.

HORIZONS 2018

  • Build a team with talented radiologists, physicists and engineers to develop cutting-edge imaging research.
  • Incorporate imaging biomarkers in translational research projects at VHIO as well as other leading research centers.
  • Develop novel imaging processing algorithms for advanced imaging analysis.

PUBLICATIONS

  1. 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.
  2. 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. Investigative Radiology. Invest Radiol. 2017 Sep 12.
  3. 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.
  4. Goodall J, Mateo J, Yuan W, Mossop H, Porta N, Miranda S, Perez-Lopez R, Dolling D, Robinson DR, Sandhu S, Fowler G, Ebbs B, Flohr P, Seed G, Rodrigues DN, Boysen G, Bertan C, Atkin M, Clarke M, Crespo M, Figueiredo I, Riisnaes R, Sumanasuriya S, Rescigno P, Zafeiriou Z, Sharp A, Tunariu N, Bianchini D, Gillman A, Lord CJ, Hall E, Chinnaiyan AM, Carreira S, de Bono JS; TOPARP-A investigators. Circulating Free DNA to Guide Prostate Cancer Treatment with PARP Inhibition. Cancer Discov. 2017 Apr 27. pii: CD-17-0261.
  5. Bianchini D, Lorente D, Rescigno P, Zafeiriou Z, Psychopaida E, O'Sullivan H, Alaras M, Kolinsky M, Sumanasuriya S, Sousa Fontes M, Mateo J, Perez Lopez R, Tunariu N, Fotiadis N, Kumar P, Tree A, Van As N, Khoo V, Parker C, Eeles R, Thompson A, Dearnaley D, de Bono JS. Effect on Overall Survival of Locoregional Treatment in a Cohort of De Novo Metastatic Prostate Cancer Patients: A Single Institution Retrospective Analysis From the Royal Marsden Hospital. Clin Genitourin Cancer. 2017 Apr 26.