Enrique Carrillo-de Santa Pau

Most highly expressed protein-coding genes have a single dominant isoform.

Although eukaryotic cells express a wide range of alternatively spliced transcripts, it is not clear whether genes tend to express a range of transcripts simultaneously across cells, or produce dominant isoforms in a manner that is either tissue-specific or regardless of tissue. To date, large-scale investigations into the pattern of transcript expression across distinct tissues have produced contradictory results. Here, we attempt to determine whether genes express a dominant splice variant at the protein level. We interrogate peptides from eight large-scale human proteomics experiments and databases and find that there is a single dominant protein isoform, irrespective of tissue or cell type, for the vast majority of the protein-coding genes in these experiments, in partial agreement with the conclusions from the most recent large-scale RNAseq study. Remarkably, the dominant isoforms from the experimental proteomics analyses coincided overwhelmingly with the reference isoforms selected by two completely orthogonal sources, the consensus coding sequence variants, which are agreed upon by separate manual genome curation teams, and the principal isoforms from the APPRIS database, predicted automatically from the conservation of protein sequence, structure, and function.

The acinar regulator Gata6 suppresses KrasG12V-driven pancreatic tumorigenesis in mice

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 acinar-ductal 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.

GATA6 regulates EMT and tumour dissemination, and is a marker of response to adjuvant chemotherapy in pancreatic cancer

Background and aims The role of GATA factors in cancer has gained increasing attention recently, but the function of GATA6 in pancreatic ductal adenocarcinoma (PDAC) is controversial. GATA6 is amplified in a subset of tumours and was proposed to be oncogenic, but high GATA6 levels are found in well-differentiated tumours and are associated with better patient outcome. By contrast, a tumour-suppressive function of GATA6 was demonstrated using genetic mouse models. We aimed at clarifying GATA6 function in PDAC. Design We combined GATA6 silencing and overexpression in PDAC cell lines with GATA6 ChIP-Seq and RNA-Seq data, in order to understand the mechanism of GATA6 functions. We then confirmed some of our observations in primary patient samples, some of which were included in the ESPAC-3 randomised clinical trial for adjuvant therapy. Results GATA6 inhibits the epithelial–mesenchymal transition (EMT) in vitro and cell dissemination in vivo. GATA6 has a unique proepithelial and antimesenchymal function, and its transcriptional regulation is direct and implies, indirectly, the regulation of other transcription factors involved in EMT. GATA6 is lost in tumours, in association with altered differentiation and the acquisition of a basal-like molecular phenotype, consistent with an epithelial-to-epithelial (ET2) transition. Patients with basal-like GATA6low tumours have a shorter survival and have a distinctly poor response to adjuvant 5-fluorouracil (5-FU)/leucovorin. However, modulation of GATA6 expression in cultured cells does not directly regulate response to 5-FU. Conclusions We provide mechanistic insight into GATA6 tumour-suppressive function, its role as a regulator of canonical epithelial differentiation, and propose that loss of GATA6 expression is both prognostic and predictive of response to adjuvant therapy.

Somatic Embryonic FGFR2 Mutations in Keratinocytic Epidermal Nevi

Journal of Investigative Dermatology (2016), Volum Department of Dermatology and Venereology, Soroka Medical Center, Beer-Sheva, Israel; Faculty of Health Sciences, Ben-Gurion University of the Negev, BeerSheva, Israel; Siaal Research Center for Family Medicine and Primary Care, Division of Community Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; Institute for Gastroenterology and Hepatology, Soroka Medical Center, Beer-Sheva, Israel; General Management, Clalit Health Services, Tel Aviv, Israel; and Department of Quality Measurements and Research, Chief Physician’s Office, Clalit Health Services, Tel-Aviv, Israel Corresponding author e-mail: Guyshallom1234@hotmail.com

Bioinformatics Analysis of Pancreas Cancer Genome in High-Throughput Genomic Technologies

The technology revolution propelled by the Human Genome Project is about to transform medicine, especially cancer treatment. Bioinformatics is essential for the interpretation of the genomic information and, as such, a fundamental element in the study of the molecular causes of pancreatic cancer pathophysiology. The aim of this chapter is to provide an overview of the bioinformatics analysis that currently is being applied to genome-wide studies in the field of pancreatic cancer. The bioinformatics methodologies cover a wide range of topics from data organization to the assessment of sample quality, the analysis of sequencing data, and the prediction of cancer driver genes and processes. This chapter illustrates the various stages of the bioinformatics analysis with actual examples taken from pancreatic cancer genome projects and includes a description of the available technologies and resources in each case. The current limitations in the interpretation of cancer genome data, difficulties in the integration of clinical and genomic data, and challenges in the interpretation of the genomic information in clinical settings are highlighted.

DNA methylation profiling identifies candidate genes for the pathogenesis of hepatosplenic T-cell lymphoma

Funding: this work was funded by the European Union’s Seventh Framework Program through the Blueprint Consortium (grant agreement 282510). MJSDs work was supported by the Leicester Experimental Cancer Medicine Centre (C325/A15575 Cancer Research UK/UK Department of Health). PG’s work was supported by a grant from the Fondation pour la Recherche Medicale, grant number “DEQ20160334875”. RS’ work was supported by the DFG in the framework of the SFB1074.