Metabolic and epigenetic states in cells can be linked when intermediary metabolism generates substrates for chromatin regulation. Kottakis et al. have found that synergistic liver kinase B1 (LKB1) loss and KRAS activation can promote mTOR-mediated serine biosynthesis pathway dependency during pancreatic tumorigenesis. The subsequent generation of S-adenosylmethionine (SAM) drives increased DNA methylation, with specific enrichment of methylation of retrotransposons that are transcriptionally silenced as a consequence. These data indicate that DNA methyltransferase inhibitors may be effective in cancers with LKB1 mutations.