RASA2 Promotes Pancreatic Cancer Metastasis by Activating TGFβ-Dependent Non-canonical Hedgehog Signaling
Taochen He, Qiangda Chen, Yanfei An, Zhihang Xu, Zhenlai Jiang, Jiande Han, Yuqi Xie, Hanyu Li, Chaoyu Pang, Jiayi Xu, Wei Gan, Haibo Wang, Yun Jin, Wenquan Wang, Xu-an Wang, Wenchuan Wu, Wenhui Lou, Hanlin Yin, Ning Pu, Liang LiuAbstract
KRAS mutations are a major driver of pancreatic ductal adenocarcinoma (PDAC). RASA2, a RAS GTPase-activating protein, modulates KRAS protein levels in wild-type contexts, suggesting it could play a potential role in PDAC. Here, we systematically investigated the biological function and molecular mechanisms of RASA2 in PDAC. Integrative analyses of multiple datasets and clinical samples demonstrated that RASA2 was consistently upregulated in KRAS-mutant PDAC and significantly associated with poor prognosis and metastatic progression. Gain- and loss-of-function studies revealed that RASA2 markedly enhanced PDAC cell migration and invasion in both KRAS-mutant and KRAS-wild-type models, suggesting that its pro-metastatic activity is largely independent of KRAS mutational status. Transcriptomic and mechanistic analyses revealed that RASA2 activated GLI1 through a TGFβ2-dependent, non-canonical Hedgehog pathway. Mechanistically, RASA2 interacted with RTF1 to promote H2BK120 ubiquitination at the TGFB2 promoter, thereby enhancing TGFβ2 transcription and activating downstream GLI1 signaling. Pharmacological inhibition of TGFβ signaling or genetic silencing of GLI1 effectively suppressed RASA2-driven migratory, invasive, and metastatic phenotypes in vitro and in vivo. Collectively, these findings reveal a mechanism by which RASA2-dependent epigenetic and transcriptional reprogramming promotes metastatic progression and nominate the RASA2– TGFβ2–GLI1 axis as a potential therapeutic target in PDAC.