The extracellular matrix drives guanylate production and protects pancreatic cancer cells from oxaliplatin-induced DNA damage.

The excessive production of extracellular matrix (ECM) and the metabolic adaptations in pancreatic ductal adenocarcinoma (PDAC) contribute individually to enhanced chemoresistance, marked tumor progression, and dismal patient survival. However, ECM-driven metabolic alterations that promote chemoresistance in PDAC are so far unexplored. Here, we use in vitro-generated ECM bioscaffolds that recapitulate cell-ECM interactions and induce broad metabolic alterations in PDAC cells. High-throughput integration of multiomics datasets coupled with metabolic tracing showed that the ECM enhances the generation of guanylates in PDAC cells, the accumulation of which alleviates oxaliplatin-induced DNA damage, and boosts PDAC cell proliferation. These events are guided by the guanosine monophosphate (GMP)-producing enzymes inosine monophosphate dehydrogenase (IMPDH) and guanosine monophosphate synthase (GMPS), the expression of which correlated with that of matrisomal and DNA repair genes in samples from patients with PDAC. We propose that targeting ECM-driven metabolic processes, such as the enhanced IMPDH activity, may be an effective therapeutic approach for patients with PDAC to bypass the negative side effects of direct targeting of the ECM itself.