LPA released from dying cancer cells after chemotherapy inactivates Hippo signaling and promotes pancreatic cancer cell repopulation

Abstract Gemcitabine-based chemotherapy remains the cornerstone of comprehensive treatment for pancreatic ductal adenocarcinoma (PDAC). A significant bottleneck in tumor therapeutic efficacy is tumor repopulation, which is also considered one of the key reasons for drug resistance and recurrence. Previous investigations have highlighted the crucial role of the Hippo pathway in the tumorigenesis and progression of PDAC, with lysophosphatidic acid (LPA) regulating the Hippo pathway to promote cancer. However, the effect of the Hippo signaling pathway on tumor repopulation in PDAC has not been reported. In this study, we constructed a model where dose-dependent gemcitabine-induced dying cells release LPA, which promotes the proliferation, clonal formation, and invasion of pancreatic cancer cells. Mechanistic studies show that gemcitabine and LPA inhibit the phosphorylation of Yes-associated protein 1 (YAP1) and induce the inactivation of the Hippo pathway. Overexpression of YAP1 significantly upregulates the mRNA and protein expression levels of autocrine motility factor (ATX), inducing pancreatic cancer cells to release LPA, forming a positive feedback loop of LPA-Hippo to promote the re-proliferation of residual tumor cells. At the same time, it was found that inhibiting LPA and YAP1 expression can also increase the sensitivity of pancreatic cancer to gemcitabine. Thus, this study suggests that targeting the LPA-YAP1 signaling pathway may represent an effective strategy to improve the comprehensive therapeutic efficacy of PDAC.