title: Re-engineering the Pancreas Tumor Microenvironment: A "Regenerative Program" Hacked.
abstract: The "hallmarks" of pancreatic ductal adenocarcinoma (PDAC) include proliferative, invasive, and metastatic tumor cells and an associated dense desmoplasia comprised of fibroblasts, pancreatic stellate cells, extracellular matrix, and immune cells. The oncogenically activated pancreatic epithelium and its associated stroma are obligatorily interdependent, with the resulting inflammatory and immunosuppressive microenvironment contributing greatly to the evolution and maintenance of PDAC. The peculiar pancreas-specific tumor phenotype is a consequence of oncogenes hacking the resident pancreas regenerative program, a tissue-specific repair mechanism regulated by discrete super enhancer networks. Defined as genomic regions containing clusters of multiple enhancers, super enhancers play pivotal roles in cell/tissue specification, identity, and maintenance. Hence, interfering with such super enhancer-driven repair networks should exert a disproportionately disruptive effect on tumor versus normal pancreatic tissue. Novel drugs that directly or indirectly inhibit processes regulating epigenetic status and integrity, including those driven by histone deacetylases, histone methyltransferase and hydroxylases, DNA methyltransferases, various metabolic enzymes, and bromodomain and extraterminal motif proteins, have shown the feasibility of disrupting super enhancer-dependent transcription in treating multiple tumor types, including PDAC. The idea that pancreatic adenocarcinomas rely on embedded super enhancer transcriptional mechanisms suggests a vulnerability that can be potentially targeted as novel therapies for this intractable disease.Clin Cancer Res; 23(7); 1647-55. ©2017 AACRSee all articles in thisCCR Focussection, "Pancreatic Cancer: Challenge and Inspiration."
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom. evans@salk.edu gie20@cam.ac.uk.
authors.forename: Gerard I
authors.initials: GI
authors.lastname: Evan
authors.affiliation: Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California.
authors.forename: Nasun
authors.initials: N
authors.lastname: Hah
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Trevor D
authors.initials: TD
authors.lastname: Littlewood
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Sodir
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Tania
authors.initials: T
authors.lastname: Campos
authors.affiliation: Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California.
authors.forename: Michael
authors.initials: M
authors.lastname: Downes
authors.affiliation: Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California. evans@salk.edu gie20@cam.ac.uk.|Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, California.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D004742:Enhancer Elements, Genetic; D006801:Humans; D058990:Molecular Targeted Therapy; D010179:Pancreas / Q000473:pathology; D058954:Pancreatic Stellate Cells / Q000473:pathology; D059016:Tumor Microenvironment / Q000235:genetics*