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Proc Natl Acad Sci U S A. 2017 Jan 31;114(5):1129-1134. doi: 10.1073/pnas.1620164114. Epub 2017 Jan 17.

Stromal cues regulate the pancreatic cancer epigenome and metabolome.

Author information

1
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037.
2
Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
3
Storr Liver Centre, Westmead Millennium Institute, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia.
4
Department of Medicine/Hematology and Oncology, University of California, San Francisco, CA 94143.
5
Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02115.
6
Department of Radiation Oncology, New York University School of Medicine, New York, NY 10016.
7
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037; evans@salk.edu downes@salk.edu.
8
Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037.

Abstract

A fibroinflammatory stromal reaction cooperates with oncogenic signaling to influence pancreatic ductal adenocarcinoma (PDAC) initiation, progression, and therapeutic outcome, yet the mechanistic underpinning of this crosstalk remains poorly understood. Here we show that stromal cues elicit an adaptive response in the cancer cell including the rapid mobilization of a transcriptional network implicated in accelerated growth, along with anabolic changes of an altered metabolome. The close overlap of stroma-induced changes in vitro with those previously shown to be regulated by oncogenic Kras in vivo suggests that oncogenic Kras signaling-a hallmark and key driver of PDAC-is contingent on stromal inputs. Mechanistically, stroma-activated cancer cells show widespread increases in histone acetylation at transcriptionally enhanced genes, implicating the PDAC epigenome as a presumptive point of convergence between these pathways and a potential therapeutic target. Notably, inhibition of the bromodomain and extraterminal (BET) family of epigenetic readers, and of Bromodomain-containing protein 2 (BRD2) in particular, blocks stroma-inducible transcriptional regulation in vitro and tumor progression in vivo. Our work suggests the existence of a molecular "AND-gate" such that tumor activation is the consequence of mutant Kras and stromal cues, providing insight into the role of the tumor microenvironment in the origin and treatment of Ras-driven tumors.

KEYWORDS:

BRD2; cancer metabolism; histone acetylation; pancreatic ductal adenocarcinoma; tumor microenvironment

PMID:
28096419
PMCID:
PMC5293019
DOI:
10.1073/pnas.1620164114
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

M.H.S., R.T.Y., N.D., A.R.A., M.D., and R.M.E. are coinventors of technologies using BET inhibitors and may be entitled to royalties. A.C.K. is an inventor on patents pertaining to Kras regulated metabolic pathways; redox control pathways in pancreatic cancer, targeting GOT1 as a therapeutic approach; and the autophagic control of iron metabolism. A.C.K. is on the Scientific Advisory Board of Cornerstone Pharmaceuticals and is a founder of Vescor Therapeutics.

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