Inactivation of cancer-associated-fibroblasts (CAF) disrupts oncogenic signaling in pancreatic cancer cells and promotes its regression

Resident fibroblasts that contact tumor epithelial cells (TEC) can become irreversibly activated as cancer-associated-fibroblasts (CAF) which stimulate oncogenic signaling in TEC. In this study, we evaluated the crosstalk between CAF and TEC isolated from tumors generated in a mouse model of KRAS/mutp53-induced pancreatic cancer (KPC mice). Transcriptomic profiling conducted after treatment with the anticancer compound Minnelide revealed deregulation of the TGF-β signaling pathway in CAF, resulting in an apparent reversal of their activated state to a quiescent, non-proliferative state. TEC exposed to media conditioned by drug-treated CAF exhibited a decrease in oncogenic signaling as manifested by downregulation of the transcription factor Sp1. This inhibition was rescued by treating TEC with TGF-β. Given promising early clinical studies with minnelide, our findings suggest that approaches to inactivate CAF and prevent tumor-stroma crosstalk may offer a viable strategy to treat pancreatic cancer. 

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