KRAS-PIP5K1A-SDC1 axis regulates nutrient scavenging in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with limited treatment options and a five-year survival rate of 13%. A defining characteristic of PDAC is its ability to survive and proliferate in nutrient-deprived environments. This is driven by metabolic reprogramming induced by mutant KRAS, which is present in over 90% of cases. However, the mechanism by which mutant KRAS coordinates the metabolic adaptation remains incompletely understood. We have discovered recently that mutant KRAS directly interacts with Phosphatidylinositol-4-Phosphate 5-Kinase Type I Alpha (PIP5K1A), a lipid kinase responsible for generating phosphoinositide phosphatidylinositol 4,5-bisphosphate (PI4,5P 2 ) and enhances its enzymatic activity. Upon activation by mutant KRAS, PIP5K1A generates elevated levels of PI4,5P 2 at the plasma membrane, allowing PI4,5P 2 to associate with Syndecan-1 (SDC1), a transmembrane heparan sulfate proteoglycan. The goal of this study is to define the roles of SDC1 and PIP5K1A in two major nutrient acquisition pathways: macropinocytosis-mediated uptake of extracellular proteins and SDC1-dependent regulation of Glucose Transporter 1 (GLUT1), to promote enhanced glucose uptake in pancreatic cancer cells. In CFPAC-II cells, we observed the co-localization of PI4,5P 2 , PIP5K1A, KRAS, and SDC1 at membrane ruffles, consistent with macropinocytic structures. In-vitro binding assays demonstrated a direct interaction between the SDC1 extracellular domain and nutrient transporters GLUT1 and CD98. Additionally, glucose uptake assays showed that knockdown of either SDC1 or PIP5K1A significantly decreased glucose uptake in KPC cells. Together, these findings identify a novel KRAS-PIP5K1A-SDC1 signaling axis that regulates nutrient acquisition in PDAC, highlighting a potential therapeutic strategy to disrupt nutrient scavenging in KRAS-driven pancreatic cancer.