PROGRAMMED ADDICTION OF PANCREATIC CANCER TO NUCLEOTIDE METABOLISM BY THE TUMOR MICROENVIRONMENT

Pancreatic ductal adenocarcinoma (PDAC) is one of the fastest growing malignancy, yet PDAC cells face a harsh tumor microenvironment (TME) of poor nutrient availability. To adapt, they were shown to exploit stellate cells, the predominant stromal cells, for growth-promoting nutrients. However, there is inadequate understanding of tumor-stellate cells crosstalks in sustaining nucleotide synthesis – a substrate and energy-intensive process. Using patient-derived co-cultured models that closely recapitulated PDAC histology, KRAS genotype and gemcitabine response, I uncover that stellate cells strategized nutrient sharing and partitioning of nucleotide substrates to fuel PDAC growth. By reducing environmental folic acid, this decreases folic acid-responsive TYMS and drives PDAC cells to salvage stellate-derived thymidine. Corroboratively, stellate cells provide aspartate through SLC1A3-mediated uptake in PDAC cells and this enhances GMP synthesis. My findings highlight the need to limit stellate-supplied nutrients in future therapeutic design for PDAC.

Author dc:creator

• SHIRLEY LAM

• Pancreatic cancer, Tumor-stellate crosstalk, Nucleotide synthesis