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, dramatic tumor progression and dismal patient survival. However, the ECM-driven metabolic alterations that promote chemoresistance in PDAC are less well described. Here, we use in-vitro-generated ECM bio-scaffolds that recapitulate cell-ECM interactions and induce broad metabolic alterations in PDAC cells. High-throughput integration of multi-omics datasets coupled with metabolic tracing showed that the ECM favors the accumulation of guanylates in PDAC cells and alleviation of oxaliplatin-induced DNA damage, thus supporting PDAC cell proliferation. This is controlled by the GMP-producing enzyme IMPDH, the expression of which was upregulated in resected PDAC tissue from patients who displayed low survival. We propose that targeting ECM-modulated metabolic processes in PDAC may be a more effective and safer approach, without the negative side effects of direct targeting of the ECM itself. Overall design: RNAseq profiling of tumor cells isolated from a pancreatic ductal adenocarcinoma murine model when cultivated on the extracellular matrix of patient-derived cancer-associated fibroblasts compared to when grown on matrix-free tissue culture vessels.