Microenvironmental cues co-regulate pancreatic cancer metabolism and histone acetylation

To investigate the paracrine effects of stromal elements on cancer cells, we developed a “stromal” culture system, which incorporates structural and diffusible stroma-derived elements into homotypic cultures amenable to functional genomics and metabolomics. We show that microenvironmental cues co-regulate cancer metabolism and gene expression. Stromal inputs broadly influence histone acetylation in the cancer epigenome, coinciding with induction of genes implicated in anabolic metabolism and inflammation. The gene expression and metabolic changes induced by stromal factors overlap with those previously identified following oncogenic Kras, suggesting functional complementarity between cell-autonomous and microenvironmental pathways. We implicate the BET family of epigenetic readers as key transducers of stromal inputs to drive alterations in gene expression and suggest paracrine epigenome regulation as a conduit through which stromal signals drive metabolic and immune adaptation to a challenging tumor microenvironment. Comparison of histone acetylation marks H3K9ac and H3K27ac in MIAPaCa2 cells cultured under 3D stromal and astromal conditions