Epithelial Carcinogenesis Group

Madrid, Spain

Epithelial Carcinogenesis Group

Madrid, Spain
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Aguilar H.,Catalan Institute of Nanoscience and Nanotechnology | Sole X.,lHospitalet | Bonifaci N.,lHospitalet | Serra-Musach J.,lHospitalet | And 8 more authors.
Oncogene | Year: 2010

Endocrine therapies targeting the proliferative effect of 17Β-estradiol through estrogen receptor α (ERα) are the most effective systemic treatment of ERα-positive breast cancer. However, most breast tumors initially responsive to these therapies develop resistance through molecular mechanisms that are not yet fully understood. The long-term estrogen-deprived (LTED) MCF7 cell model has been proposed to recapitulate acquired resistance to aromatase inhibitors in postmenopausal women. To elucidate this resistance, genomic, transcriptomic and molecular data were integrated into the time course of MCF7-LTED adaptation. Dynamic and widespread genomic changes were observed, including amplification of the ESR1 locus consequently linked to an increase in ERα. Dynamic transcriptomic profiles were also observed that correlated significantly with genomic changes and were predicted to be influenced by transcription factors known to be involved in acquired resistance or cell proliferation (for example, interferon regulatory transcription factor 1 and E2F1, respectively) but, notably, not by canonical ERα transcriptional function. Consistently, at the molecular level, activation of growth factor signaling pathways by EGFR/ERBB/AKT and a switch from phospho-Ser118 (pS118)-to pS167-ERα were observed during MCF7-LTED adaptation. Evaluation of relevant clinical settings identified significant associations between MCF7-LTED and breast tumor transcriptome profiles that characterize ERα-negative status, early response to letrozole and tamoxifen, and recurrence after tamoxifen treatment. In accordance with these profiles, MCF7-LTED cells showed increased sensitivity to inhibition of FGFR-mediated signaling with PD173074. This study provides mechanistic insight into acquired resistance to endocrine therapies of breast cancer and highlights a potential therapeutic strategy. © 2010 Macmillan Publishers Limited All rights reserved.

Fernandez L.C.,Epithelial Carcinogenesis Group | Real F.X.,University Pompeu Fabra
Nature Reviews Cancer | Year: 2016

Diversity is the basis of fitness selection. Although the genome of an individual is considered to be largely stable, there is theoretical and experimental evidence-both in model organisms and in humans-that genetic mosaicism is the rule rather than the exception. The continuous generation of cell variants, their interactions and selective pressures lead to life-long tissue dynamics. Individuals may thus enjoy 'clonal health', defined as a clonal composition that supports healthy morphology and physiology, or suffer from clonal configurations that promote disease, such as cancer. The contribution of mosaicism to these processes starts during embryonic development. In this Opinion article, we argue that the road to cancer might begin during these early stages. © 2016 Macmillan Publishers Limited.

Martinelli P.,Epithelial Carcinogenesis Group | Canamero M.,Comparative Pathology Unit | Del Pozo N.,Epithelial Carcinogenesis Group | Madriles F.,Epithelial Carcinogenesis Group | And 3 more authors.
Gut | Year: 2013

Objectives: Previous studies have suggested an important role of the transcription factor Gata6 in endocrine pancreas, while GATA6 haploinsufficient inactivating mutations cause pancreatic agenesis in humans. We aimed to analyse the effects of Gata6 inactivation on pancreas development and function. Design: We deleted Gata6 in all epithelial cells in the murine pancreas at the onset of its development. Acinar proliferation, apoptosis, differentiation and exocrine functions were assessed using reverse transcriptase quantitative PCR (RT-qPCR), chromatin immunoprecipitation, immunohistochemistry and enzyme assays. Adipocyte transdifferentiation was assessed using electron microscopy and genetic lineage tracing. Results: Gata6 is expressed in all epithelial cells in the adult mouse pancreas but it is only essential for exocrine pancreas homeostasis: while dispensable for pancreatic development after e10.5, it is required for complete acinar differentiation, for establishment of polarity and for the maintenance of acinar cells in the adult. Gata6 regulates directly the promoter of genes coding for digestive enzymes and the transcription factors Rbpjl and Mist1. Upon pancreas-selective Gata6 inactivation, massive loss of acinar cells and fat replacement take place. This is accompanied by increased acinar apoptosis and proliferation, acinar-to-ductal metaplasia and adipocyte transdifferentiation. By contrast, the endocrine pancreas is spared. Conclusions: Our data show that Gata6 is required for the complete differentiation of acinar cells through multiple transcriptional regulatory mechanisms. In addition, it is required for the maintenance of the adult acinar cell compartment. Our studies suggest that GATA6 alterations may contribute to diseases of the human adult exocrine pancreas.

Hermann P.C.,Stem Cells and Cancer Group | Sancho P.,Stem Cells and Cancer Group | Canamero M.,Comparative Pathology Core Unit | Martinelli P.,Epithelial Carcinogenesis Group | And 14 more authors.
Gastroenterology | Year: 2014

Background & Aims Although smoking is a leading risk factor for pancreatic ductal adenocarcinoma (PDAC), little is known about the mechanisms by which smoking promotes initiation or progression of PDAC.Methods We studied the effects of nicotine administration on pancreatic cancer development in Kras+/LSLG12Vgeo;Elas-tTA/tetO-Cre (Ela-KRAS) mice, Kras+/LSLG12D;Trp53+/LSLR172H;Pdx-1-Cre (KPC) mice (which express constitutively active forms of KRAS), and C57/B6 mice. Mice were given nicotine for up to 86 weeks to produce blood levels comparable with those of intermediate smokers. Pancreatic tissues were collected and analyzed by immunohistochemistry and reverse transcriptase polymerase chain reaction; cells were isolated and assayed for colony and sphere formation and gene expression. The effects of nicotine were also evaluated in primary pancreatic acinar cells isolated from wild-type, nAChR7a-/-, Trp53-/-, and Gata6-/-;Trp53-/- mice. We also analyzed primary PDAC cells that overexpressed GATA6 from lentiviral expression vectors.Results Administration of nicotine accelerated transformation of pancreatic cells and tumor formation in Ela-KRAS and KPC mice. Nicotine induced dedifferentiation of acinar cells by activating AKT-ERK-MYC signaling; this led to inhibition of Gata6 promoter activity, loss of GATA6 protein, and subsequent loss of acinar differentiation and hyperactivation of oncogenic KRAS. Nicotine also promoted aggressiveness of established tumors as well as the epithelial-mesenchymal transition, increasing numbers of circulating cancer cells and their dissemination to the liver, compared with mice not exposed to nicotine. Nicotine induced pancreatic cells to acquire gene expression patterns and functional characteristics of cancer stem cells. These effects were markedly attenuated in K-Ras+/LSL-G12D;Trp53+/LSLR172H;Pdx-1-Cre mice given metformin. Metformin prevented nicotine-induced pancr.eatic carcinogenesis and tumor growth by up-regulating GATA6 and promoting differentiation toward an acinar cell program.Conclusions In mice, nicotine promotes pancreatic carcinogenesis and tumor development via down-regulation of Gata6 to induce acinar cell dedifferentiation. © 2014 by the AGA Institute.

Gerlinger M.,Institute of Cancer Research | Gerlinger M.,Royal Marsden Hospital | Catto J.W.,University of Sheffield | Orntoft T.F.,Aarhus University Hospital | And 5 more authors.
European Urology | Year: 2015

Context Intratumour heterogeneity (ITH) can impair the precise molecular analysis of tumours and may contribute to difficulties encountered in cancer biomarker qualification and treatment personalisation. Objective This review summarises the evidence for genetic ITH in renal, bladder, and prostate carcinomas and potential strategies to address the clinical and translational research challenges arising from ITH. Evidence acquisition Publications that assessed ITH in the relevant urologic cancers were identified in a literature review. Evidence synthesis ITH with functionally distinct tumour subclones has been identified in all three tumour types. Heterogeneity of actionable genetic changes and of prognostic biomarkers between different tumour regions in the same patient suggests limitations of single biopsy-based molecular analyses for precision medicine approaches. Evolutionary constraints may differ between patients and may allow the prediction of specific evolutionary trajectories. Conclusions Assessment of multiple tumour regions for precision medicine purposes, monitoring of subclonal dynamics over time, and the preferential targeting of genetic alterations located on the trunk of the phylogenetic tree of individual cancers may accelerate the development of personalised medicine strategies and improve our understanding of treatment failure. Patient summary Genetic alterations can be heterogeneous within urologic tumours, complicating their use as biomarkers for treatment personalisation. We present novel strategies to address these challenges. © 2014 European Association of Urology. All rights reserved.

Martinelli P.,Epithelial Carcinogenesis Group | Madriles F.,Epithelial Carcinogenesis Group | Canamero M.,Comparative Pathology Unit | Carrillo-De Santa Pau E.,Epithelial Carcinogenesis Group | And 4 more authors.
Gut | Year: 2016

Background and aims: Gata6 is required to complete and maintain acinar differentiation in the mouse pancreas. Pancreas-specific Gata6 ablation during development causes extensive and persistent acinarductal metaplasia, which is considered an initial step of mutant KRas-driven carcinogenesis. Therefore, the Gata6-null pancreas might represent a tumour-prone environment. We investigated whether Gata6 plays a role during pancreatic tumorigenesis. Design: We analysed genetically engineered mouse models and human pancreatic ductal adenocarcinoma (PDAC) cell lines, using a combination of histopathological studies, genome-wide expression and chromatin immunoprecipitation experiments to understand the role of Gata6 in the initiation and progression of KRasG12V-driven tumours Results We show that Gata6 maintains the acinar differentiation programme, both directly and indirectly, and it concomitantly suppresses ectopic programmes in the pancreas. Gata6 ablation renders acinar cells more sensitive to KRasG12V, thereby accelerating tumour development. Gata6 expression is spontaneously lost in a mouse model of KRasG12V-driven PDAC, in association with altered cell differentiation. Using a combination of ChIP-Seq and RNA-Seq, we show that Gata6 exerts its tumour-suppressive effect through the promotion of cell differentiation, the suppression of inflammatory pathways, and the direct repression of cancer-related pathways. Among them is the epidermal growth factor receptor (EGFR) pathway, the activity of which is upregulated in the normal and preneoplastic Gata6-null pancreas. Accordingly, GATA6-silencing in human PDAC cells leads to an upregulation of EGFR. Conclusions: We propose that, in the pancreas, Gata6 acts as a tumour suppressor by enforcing acinar cell differentiation, by directly and indirectly repressing ectopic differentiation programmes, and by regulating crucial cancer-related gene expression pathways.

Flandez M.,Epithelial Carcinogenesis Group | Cendrowski J.,Epithelial Carcinogenesis Group | Canamero M.,Histopathology Core Unit | Salas A.,Hospital Mutua Terrassa | And 3 more authors.
Gut | Year: 2014

Objectives: Nr5a2 participates in biliary acid metabolism and is a major regulator of the pancreatic exocrine programme. Single nucleotide polymorphisms in the vicinity of NR5A2 are associated with the risk of pancreatic ductal adenocarcinoma (PDAC). Aims: To determine the role of Nr5a2 in pancreatic homeostasis, damage-induced regeneration and mutant KRas-driven pancreatic tumourigenesis. Design: Nr5a2+/- and KRasG12V;Ptf1a- Cre;Nr5a2+/- mice were used to investigate whether a full dose of Nr5a2 is required for normal pancreas development, recovery from caerulein-induced pancreatitis, and protection from tumour development. Results: Adult Nr5a2+/- mice did not display histological abnormalities in the pancreas but showed a more severe acute pancreatitis, increased acino-ductal metaplasia and impaired recovery from damage. This was accompanied by increased myeloid cell infiltration and proinflammatory cytokine gene expression, and hyperactivation of nuclear factor.b and signal transducer and activator of transcription 3 signalling pathways. Induction of multiple episodes of acute pancreatitis was associated with more severe damage and delayed regeneration. Inactivation of one Nr5a2 allele selectively in pancreatic epithelial cells was sufficient to cause impaired recovery from pancreatitis. In comparison with Nr5a2+/+ mice, KRasG12V;Ptf1aCre/+; Nr5a2 +/- mice showed a non-statistically significant increase in the area affected by preneoplastic lesions. However, a single episode of acute pancreatitis cooperated with loss of one Nr5a2 allele to accelerate KRasG12V-driven development of preneoplastic lesions. Conclusions A full Nr5a2 dose is required to restore pancreatic homeostasis upon damage and to suppress the KRasG12V-driven mouse pancreatic intraepithelial neoplasia progression, indicating that Nr5a2 is a novel pancreatic tumour suppressor. Nr5a2 could contribute to PDAC through a role in the recovery from pancreatitisinduced damage.

Malats N.,Genetic and Molecular Epidemiology Group | Real F.X.,Epithelial Carcinogenesis Group | Real F.X.,University Pompeu Fabra
Hematology/Oncology Clinics of North America | Year: 2015

Bladder cancer incidence is higher in old men, shows geographic variation, and is mostly an environmental disease. Cigarette smoking, occupational exposures, water arsenic, Schistosoma haematobium infestation, and some medications are the best established risk factors. Low-penetrance genetic factors also contribute to its origin, some through interaction with environmental factors. Bladder cancer has high prevalence and a low mortality, being largely a chronic disease. Data on environmental and genetic factors involved in the disease outcome are inconclusive. © 2015 Elsevier Inc.

Masson-Lecomte A.,Genetic and Molecular Epidemiology Group | Masson-Lecomte A.,French Institute of Health and Medical Research | Rava M.,Genetic and Molecular Epidemiology Group | Real F.X.,Epithelial Carcinogenesis Group | And 5 more authors.
European Urology | Year: 2014

Context Host immune response has an impact on tumour development and progression. There is interest in the use of inflammatory biomarkers (InfBMs) in cancer care. Although several studies assessing the potential prognostic value of InfBMs in cancer have been published in the past decades, they have had no impact on the management of patients with urothelial bladder carcinoma (UBC).Objective To review and summarise the scientific literature on the prognostic value of tumour, serum, urine, and germline DNA InfBMs on UBC. Evidence acquisition A systematic review of the literature was performed searching the Medline and Embase databases for original articles published between January 1975 and November 2013. The main inclusion criterion was the provision of a survival analysis (Kaplan-Meier and/or Cox) according to the Reporting Recommendations for Tumor Marker Prognostic Studies guidelines for the assessment of prognostic markers. We focused on markers assessed at least twice in the literature. Findings are reported following Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. Evidence synthesis Overall, 34 publications, mostly retrospective, fulfilled the main inclusion criterion. Main limitations of these studies were missing relevant information about design or analysis and heterogeneous methodology used. Inflammatory cells, costimulatory molecules in tumour cells, and serum cytokines showed prognostic significance, mainly in univariable analyses. High C-reactive protein values were consistently reported as an independent prognostic factor for mortality in invasive UBC.Conclusions There is a dearth of studies on InfBMs in UBC compared with other tumour types. Evidence suggests that InfBMs may have an impact on the management of patients with UBC. Currently, methodological drawbacks of the studies limit the translational potential of results.Patient summary In this review, we analysed studies evaluating the impact of inflammatory response on bladder cancer progression. Despite methodological limitations, some inflammatory biomarkers should be further analysed because they hold promise to improve patient care. © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Ferrer J.,Imperial College London | Ferrer J.,Institute dInvestigacions Biomediques August Pi i Sunyer IDIBAPS | Real F.X.,Epithelial Carcinogenesis Group | Real F.X.,University Pompeu Fabra
EMBO Journal | Year: 2016

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most devastating human diseases. There is consequently a pressing need to understand its molecular underpinnings, which should enable new preventive and therapeutic strategies. A new study in The EMBO Journal (Diaferia et al, 2016) maps the transcriptome and epigenetic landscape associated with distinct PDAC grades and identifies cis- and trans-regulatory elements in tumour progression. A new genomewide study identifies cis- and trans-regulatory elements in pancreatic ductal carcinoma, thus shedding light on the mechanisms underlying tumour progression. © 2016 The Authors.

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