Microenvironment and resistance Lab


​David G. Molleví – Group leader
Berta Laquente – Associated Clinical investigator
Nerea Albert – PhD student
Gemma García – PhD student
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The research group studies the influence of microenvironment, and particularly carcinoma-associated fibroblasts (CAFs) on tumorigenesis in highly desmoplastic tumours, mainly Pancreatic Adenocarcinoma and Metastatic Colorectal Carcinoma (mCRC).
What desmoplasia is? Desmoplasia is a histological feature characterised by an increase in the production of specific collagens, fibronectin, glycosaminoglycans, proteoglycans and other extracellular matrix components, and an increase in the number of mesenchymal cells, especially CAFs. CAFs are therefore a type of myofibroblasts characterised by their morphology, independently of their location, and by the expression of a-SMA, vimentin, PDGFRB and FAP (Fibroblast Activating Protein), among other markers. However, their expression pattern may vary markedly depending on their location. In other terms, the fibroblasts have been said to present topographic differentiation that is due to the initial separation of the mesoderm during embryogenesis. The quantity is associated with the prognosis in different types of tumours. However, recent results suggest that qualitative aspects are more important than quantitative ones, with special consequences on prognosis and response to treatment.
Moreover, the tumoral stroma is a potential therapeutic target since its elimination or short-circuiting would remove the protection these cells confer on tumour cells. To date, various experimental strategies have been reported, but none with any notable success. Interestingly, recent works in pancreatic cancer call into question the role of CAFs as protumorogenic instigator and some authors argue that they might be acting as a host defence to constraint the tumour growth. Our experience with colorectal tumours suggests that CAFs are heterogeneous cells, and despite having common biomarkers may differentially express other proteins that characterise distinct subpopulations with different characteristics and functions, some being protumorigenic and other tumour-suppressive, and the net balance between such subpopulations is crucial for prognosis and drug response.
Therefore, the main research interests of the group are:
- Discovery of stromal biomarkers for response prediction in pancreatic and colorectal adenocarcinomas.
- Targeting specific CAFs as therapeutic strategy in desmoplastic tumours.
www.ncbi.nlm.nih.gov/pubmed/?term=Mollevi+DG​​

​Selected Publications

Prediction of pathological response to neoadjuvant treatment in rectal cancer with a two-protein immunohistochemical score derived from stromal gene-profiling. Gonçalves-Ribeiro S, Sanz-Pamplona R, Vidal A, Sanjuan X, Guillem Díaz Maroto N, Soriano A, Guardiola J, Albert N, Martínez-Villacampa M, López I, Santos C, Serra-Musach J, Salazar R, Capella G, Villanueva A, Mollevi DG. Ann Oncol 2017 Sep 1; 28(9):2160-2168. PMID: 28911071

Carcinoma-associated fibroblasts affect sensitivity to oxaliplatin and 5FU in colorectal cancer cells. Gonçalves-Ribeiro S, Díaz-Maroto NG, Berdiel-Acer M, Soriano A, Guardiola J, Martínez-Villacampa M, Salazar R, Capellà G, Villanueva A, Martínez-Balibrea E, Molleví DG. Oncotarget. 2016 Sep 13;7(37):59766-59780. doi: 10.18632/oncotarget.11121.

A Vulnerability of a Subset of Colon Cancers with Potential Clinical Utility. Vecchione L, Gambino V, Raaijmakers J, Schlicker A, Fumagalli A, Russo M, Villanueva A, Beerling E, Bartolini A, Mollevi DG, El-Murr N, Chiron M, Calvet L, Nicolazzi C, Combeau C, Henry C, Simon IM, Tian S, in 't Veld S, D'ario G, Mainardi S, Beijersbergen RL, Lieftink C, Linn S, Rumpf-Kienzl C, Delorenzi M, Wessels L, Salazar R, Di Nicolantonio F, Bardelli A, van Rheenen J, Medema RH, Tejpar S, Bernards R. Cell. 2016 Apr 7;165(2):317-30. doi: 10.1016/j.cell.2016.02.059.

Mutanome and expression of immune response genes in microsatellite stable colon cancer. Sanz-Pamplona R, Gil-Hoyos R, López-Doriga A, Alonso MH, Aussó S, Molleví DG, Santos C, Sanjuán X, Salazar R, Alemany R, Moreno V. Oncotarget. 2016 Apr 5;7(14):17711-25. doi: 10.18632/oncotarget.7293. PMID: 26871478

Differences between CAFs and their paired NCF from adjacent colonic mucosa reveal functional heterogeneity of CAFs, providing prognostic information. Berdiel-Acer M, Sanz-Pamplona R, Calon A, Cuadras D, Berenguer A, Sanjuan X, Paules MJ, Salazar R, Moreno V, Batlle E, Villanueva A, Molleví DG. Mol Oncol. 2014 Oct;8(7):1290-305. doi: 10.1016/j.molonc.2014.04.006. PMID: 24839936

A monotonic and prognostic genomic signature from fibroblasts for colorectal cancer initiation, progression, and metastasis. Berdiel-Acer M, Cuadras D, Díaz-Maroto NG, Sanjuan X, Serrano T, Berenguer A, Moreno V, Gonçalves-Ribeiro S, Salazar R, Villanueva A, Molleví DG. Mol Cancer Res. 2014 Sep;12(9):1254-66. doi: 10.1158/1541-7786.MCR-14-0121. PMID: 24829396

A 5-gene classifier from the carcinoma-associated fibroblast transcriptomic profile and clinical outcome in colorectal cancer.Berdiel-Acer M, Berenguer A, Sanz-Pamplona R, Cuadras D, Sanjuan X, Paules MJ, Santos C, Salazar R, Moreno V, Capella G, Villanueva A, Molleví DG. Oncotarget. 2014 Aug 15;5(15):6437-52. PMID: 25115384

Aberrant gene expression in mucosa adjacent to tumor reveals a molecular crosstalk in colon cancer. Sanz-Pamplona R, Berenguer A, Cordero D, Molleví DG, Crous-Bou M, Sole X, Paré-Brunet L, Guino E, Salazar R, Santos C, de Oca J, Sanjuan X, Rodriguez-Moranta F, Moreno V. Mol Cancer. 2014 Mar 5;13:46. doi: 10.1186/1476-4598-13-46. PMID: 24597571

Lurbinectedin (PM01183), a new DNA minor groove binder, inhibits growth of orthotopic primary graft of cisplatin-resistant epithelial ovarian cancer. Vidal A, Muñoz C, Guillén MJ, Moretó J, Puertas S, Martínez-Iniesta M, Figueras A, Padullés L, García-Rodriguez FJ, Berdiel-Acer M, Pujana MA, Salazar R, Gil-Martin M, Martí L, Ponce J, Molleví DG, Capella G, Condom E, Viñals F, Huertas D, Cuevas C, Esteller M, Avilés P, Villanueva A. Clin Cancer Res. 2012 Oct 1;18(19):5399-411. doi: 10.1158/1078-0432.CCR-12-1513. PMID: 22896654

Stromal interaction molecule 2 (STIM2) is frequently overexpressed in colorectal tumors and confers a tumor cell growth suppressor phenotype. Aytes A, Molleví DG, Martinez-Iniesta M, Nadal M, Vidal A, Morales A, Salazar R, Capellà G, Villanueva A. Mol Carcinog. 2012 Sep;51(9):746-53. doi: 10.1002/mc.20843. PMID: 22125164

Hepatic carcinoma-associated fibroblasts promote an adaptative response in colorectal cancer cells that inhibit proliferation and apoptosis: nonresistant cells die by nonapoptotic cell death. Berdiel-Acer M, Bohem ME, López-Doriga A, Vidal A, Salazar R, Martínez-Iniesta M, Santos C, Sanjuan X, Villanueva A, Molleví DG. Neoplasia. 2011 Oct;13(10):931-46. PMID: 22028619

PRL-3 overexpression in epithelial cells is induced by surrounding stromal fibroblasts. Molleví DG, Aytes A, Berdiel M, Padullés L, Martínez-Iniesta M, Sanjuan X, Salazar R, Villanueva A. Mol Cancer. 2009 Jul 8;8:46. doi: 10.1186/1476-4598-8-46. PMID: 19586538
 
PRL-3 is essentially overexpressed in primary colorectal tumours and associates with tumour aggressiveness. Molleví DG, Aytes A, Padullés L, Martínez-Iniesta M, Baixeras N, Salazar R, Ramos E, Figueras J, Capella G, Villanueva A. Br J Cancer. 2008 Nov 18;99(10):1718-25. doi: 10.1038/sj.bjc.6604747.PMID: 19002188

Bioselection of a gain of function mutation that enhances adenovirus 5 release and improves its antitumoral potency. Gros A, Martínez-Quintanilla J, Puig C, Guedan S, Molleví DG, Alemany R, Cascallo M. Cancer Res. 2008 Nov 1;68(21):8928-37. doi: 10.1158/0008-5472.CAN-08-1145. PMID: 18974137

Mutations in TP53 are a prognostic factor in colorectal hepatic metastases undergoing surgical resection. Molleví DG, Serrano T, Ginestà MM, Valls J, Torras J, Navarro M, Ramos E, Germà JR, Jaurrieta E, Moreno V, Figueras J, Capellà G, Villanueva A. Carcinogenesis. 2007 Jun;28(6):1241-6. PMID: 17259658

Hemostatic status in long-term surviving xenografts. Molleví DG, Ginestà MM, Domenech P, Serrano T, Figueras J, Jaurrieta E. Surgery. 2006 Jun;139(6):775-81. PMID: 16782434

Tumor thymidylate synthase 1494del6 genotype as a prognostic factor in colorectal cancer patients receiving fluorouracil-based adjuvant treatment. Dotor E, Cuatrecases M, Martínez-Iniesta M, Navarro M, Vilardell F, Guinó E, Pareja L, Figueras A, Molleví DG, Serrano T, de Oca J, Peinado MA, Moreno V, Germà JR, Capellá G, Villanueva A. J Clin Oncol. 2006 Apr 1;24(10):1603-11. PMID: 16575011


Projects

Título. “ Study of tumor microenvironment and its crosstalk with malignant cells in PDAC and metastatic PDAC for Gemcitabine/Nab-Paclitaxel response prediction”.
Entidad Financiadora. Celgene Corporation
Investigador Principal. David G. Molleví, Berta Laquente, ICO-IDIBELL
Fecha. 2017-2018
Cuantía de la Subvención. 131000 €
 
Título. “ Proposal to investigate LILLY LY3023414 + LY2157299 in experimental therapeutic trials in advanced mouse models of oxaliplatin sensitive and resistant colorectal cancer”.
Entidad Financiadora. Elli Lilly and CO
Investigador Principal. David G. Molleví, ICO-IDIBELL
Fecha. 2016-2018
Cuantía de la Subvención. 121500 €
 
Título. “ La depleción de subpoblaciones de fibroblastos asociados a carcinoma y el bloqueo del crosstalk con las células malignas en tumores desmoplásicos como nueva diana de tratamiento”. 
Entidad Financiadora. Instituto de Salud Carlos III-Fondo de Investigaciones Sanitarias
Investigador Principal. David G. Molleví, ICO-IDIBELL
Fecha. 2016-2018
Cuantía de la Subvención. 117000 €
 
Título. “ Efecto antitumoral de Condroitín Sulfato / Glucosamina, en modelos de cáncer colorectal resistentes a Oxaliplatino”. 
Entidad Financiadora. Bioibérica S.A.
Investigador Principal. David G. Molleví, ICO-IDIBELL
Fecha. 2015-2017
Cuantía de la Subvención. 128000 €
 
Título. “ Estudio del microambiente estromal en cáncer de recto y metástasis hepáticas para predecir la respuesta a la terapia neoadyuvante y para generar nuevas dianas terapéuticas”
Entidad Financiadora. Instituto de Salud Carlos III-Fondo de Investigaciones Sanitarias
Investigador Principal. David G. Molleví, ICO-IDIBELL
Fecha. 2011-2014
Cuantía de la Subvención. 227227 €
 
Título. “ Interacción Tumor-Estroma y Resistencia a anti-tumorales (ITERT)”. Referencia. 2014-SGR-725
Entidad Financiadora. AGAUR, Generalitat de Catalunya.
Investigador Principal y Coordinador. Oriol Casanovas, ICO-IDIBELL
Fecha. 2014-2016
Cuantía de la Subvención. 28.800 €

Título. “ Identificación y validación de una firma genética asociada a riesgo de desarrollar metástasis hepáticas en pacientes de cáncer de colon estadio II-III”. 
Entidad Financiadora. Fundación Mútua Madrileña
Investigador Principal y Coordinador. David G. Molleví, ICO-IDIBELL
Fecha. 2012-2013
Cuantía de la Subvención. 28000 €
 
Título. " Estudio del patrón global de expresión genética de miofibroblastos asociados a carcinoma en carcinomas colorectales y metástasis hepáticas: definición de un set de genes marcador pronóstico de agresividad”
Entidad Financiadora. Instituto de Salud Carlos III-Fondo de Investigaciones Sanitarias
Investigador Principal. David G. Molleví, ICO-IDIBELL
Fecha. 2008-2010
Cuantía de la Subvención. 99000 €
  • Prof. Vittorio Colantuoni (Universita degli Studi del Sannio, Benevento):  Epigenetics of EMT
  • Dr. Ian Marc Bonapace (Universita degli Studi dell’Insubria, Varese): Epigenetics of EMT

To inquire about open positions  please contact:

Dr. David G. Molleví
Program Against Cancer Therapeutic Resistance, ProCURE
Catalan Institute of Oncology
Bellvitge Biomedical Research Institute, IDIBELL
3 floor, LRT1, Hospital Duran i Reynals
Gran Via 199-203, 08907 L’Hospitalet de Llobregat
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