Yap-Myc signaling induces pancreatic stellate cell activation through regulating glutaminolysis

The accumulation of activated myofibroblastic pancreatic stellate cells (MF-PSCs) induces Pancreatic Cancer desmoplasia. These MF-PSCs are derived from quiescent pancreatic stellate cells (Q-PSCs). MF-PSCs in Pancreatic Cancer tend to Glycolysis. However, increased Glycolysis alone could not be sufficient for the increased metabolic demands of MF-PSCs. YAP and Myc signaling activation is involved in Pancreatic Cancer metabolism. Since elucidating the metabolic processes of MF-PSCs may be a promising strategy to suppress Pancreatic Cancer desmoplasia, we explored whether glutaminolysis meets the bioenergetic and biosynthetic demands of Q-PSCs converted into MF-PSCs and whether this is mediated by YAP signaling to Myc. In this study, we found that during the transdifferentiation of Q-PSCs into MF-PSCs, glutaminolysis regulatory genes were upregulated, and suppression of glutaminolysis inhibited transdifferentiation. Disrupting glutaminolysis in MF-PSCs inhibited cell growth, mitochondrial respiration, and fibrogenesis, while treatment of MF-PSCs with DKG (a glutaminolysis metabolite) reversed these activities. The expression of Glutaminase (GLS1), a rate-limiting enzyme in glutaminolysis, was upregulated by YAP overexpression. YAP upregulates Myc to regulate the expression of GLS1 in MF-PSCs. YAP and Myc inhibitors disrupted glutaminolysis and inhibited myofibroblastic activities in PSCs. Thus, Yap-Myc signaling controls glutaminolysis to activate PSCs and might be a therapeutic target for Pancreatic Cancer desmoplasia.