Stromal cues regulate the pancreatic cancer epigenome and metabolome

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.pancreatic ductal adenocarcinoma | tumor microenvironment | cancer metabolism | BRD2 | histone acetylation

Metabolic Interactions in the Tumor Microenvironment

“…Notable examples include acetyl-coenzyme A (Ac-CoA) and S-adenosyl-methionine (SAM), which provide acetyl and methyl groups, respectively, that decorate histones and DNA. Pancreatic cancer cells grown in media conditioned by activated PSCs were found to exhibit profound epigenetic changes, most notably increased acetylation-mediated gene activation [114]. Gene signatures involved in anabolic glucose metabolism were significantly activated by acetylation [115].…”

Stromal biology and therapy in pancreatic cancer: ready for clinical translation?

“…In addition, recent data suggest that CAFs induce widespread increases in histone acetylation at transcriptionally enhanced genes in tumour cells, suggesting the PDA epigenome as a potential therapeutic target of stromal cues 91. In particular, inhibition of the bromodomain and extraterminal family of epigenetic readers may be a promising therapeutic strategy in subgroups of patients with PDA 91…”

Distinguishing Closely Related Pancreatic Cancer Subtypes In Vivo by 13C Glucose MRI without Hyperpolarization

“…Targeting aberrant metabolism is more difficult as the metabolism of tumors is not limited to the tumor itself, but contains substantial contributions from the surrounding cells both directly through diffusion of metabolites across the tumor boundary 47 and indirectly through the influence of regulatory and epigenetic signals. 48 The physical microenvironment of the tumor can also affect metabolism. Deficient or improperly formed 2 vasculature often induces hypoxia in PDAC tumors 49 which can induce metabolic changes 23, 50 that would not be evident by genetic analysis alone.…”