Stromal cues regulate the pancreatic cancer epigenome and metabolome

Mara H. Sherman, Ruth T. Yu, Tiffany W. Tseng, Cristovao M. Sousa, Sihao Liu, Morgan L. Truitt, Nanhai He, Ning Ding, Christopher Liddle, Annette R. Atkins, Mathias Leblanc, Eric A. Collisson, John M. Asara, Alec C. Kimmelman, Michael Downes, Ronald M. Evans

Research output: Contribution to journalArticle

54 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1129-1134
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number5
DOIs
StatePublished - Jan 31 2017

Keywords

  • BRD2
  • Cancer metabolism
  • Histone acetylation
  • Pancreatic ductal adenocarcinoma
  • Tumor microenvironment

ASJC Scopus subject areas

  • General

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