title: Dissection of transcriptional and cis-regulatory control of differentiation in human pancreatic cancer.
abstract: The histological grade of carcinomas describes the ability of tumor cells to organize in differentiated epithelial structures and has prognostic and therapeutic impact. Here, we show that differential usage of the genomic repertoire of transcriptional enhancers leads to grade-specific gene expression programs in human pancreatic ductal adenocarcinoma (PDAC). By integrating gene expression profiling, epigenomic footprinting, and loss-of-function experiments in PDAC cell lines of different grade, we identified the repertoires of enhancers specific to high- and low-grade PDACs and the cognate set of transcription factors acting to maintain their activity. Among the candidate regulators of PDAC differentiation, KLF5 was selectively expressed in pre-neoplastic lesions and low-grade primary PDACs and cell lines, where it maintained the acetylation of grade-specific enhancers, the expression of epithelial genes such as keratins and mucins, and the ability to organize glandular epithelia in xenografts. The identification of the transcription factors controlling differentiation in PDACs will help clarify the molecular bases of its heterogeneity and progression.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy.
authors.forename: Giuseppe R
authors.initials: GR
authors.lastname: Diaferia
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Balestrieri
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Prosperini
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Nicoli
authors.affiliation: Division of Pancreatic Surgery, Humanitas Clinical Institute, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Spaggiari
authors.affiliation: Division of Pancreatic Surgery, Humanitas Clinical Institute, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Zerbi
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy gioacchino.natoli@ieo.eu.
authors.forename: Gioacchino
authors.initials: G
authors.lastname: Natoli
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology*; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005819:Genetic Markers; D006801:Humans; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
chemical_list: D005819:Genetic Markers; D014157:Transcription Factors
keywords: differentiation; enhancers; epigenetics; epithelial–mesenchymal transition; pancreatic ductal adenocarcinoma