KRAS-Mutation Driven RASA2 Promotes Pancreatic Cancer Metastasis via TGFB2-Dependent Non-Canonical Hedgehog/GLI1 Activation

KRAS mutations are a major driver of pancreatic ductal adenocarcinoma (PDAC), promoting tumor initiation, progression, and metastasis. RASA2, a Ras GTPase-activating protein, modulates KRAS protein levels in wild-type contexts, yet its role in KRAS-mutant PDAC remains unclear. Here, we systematically investigated the biological function and molecular mechanisms of RASA2 in KRAS-mutant PDAC. Integrative analyses of multiple datasets and patient-derived samples demonstrated that RASA2 is 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 enhances PDAC cell migration and invasion in both KRAS-mutant and KRAS-wild-type models, indicating that its pro-metastatic activity is largely independent of KRAS mutational status. Transcriptomic profiling and mechanistic interrogation uncovered that RASA2 activates GLI1 through a TGFB2-dependent, Sonic Hedgehog–independent non-canonical Hedgehog signaling pathway. Mechanistically, RASA2 directly interacts with the transcriptional regulator RTF1, facilitating H2BK120 ubiquitination at the TGFB2 promoter and thereby augmenting TGFB2 transcription. This epigenetic activation of TGFB2 subsequently drives non-canonical Hedgehog/GLI1 signaling to confer pro-metastatic traits. Pharmacologic inhibition of TGFB2 signaling or genetic silencing of GLI1 effectively abrogated RASA2-driven migratory, invasive, and metastatic phenotypes both in vitro and in vivo. Collectively, our findings identify RASA2 as a critical mediator of PDAC metastasis downstream of oncogenic KRAS and uncover a previously unrecognized RASA2–RTF1–H2BK120ub1–TGFB2–GLI1 signaling axis. KRAS mutation drives RASA2 upregulation, while the pro-metastatic activity of RASA2 is largely independent of KRAS mutational status. These findings reveal a previously unrecognized mechanism by which oncogenic KRAS promotes metastatic progression through RASA2-dependent epigenetic and transcriptional reprogramming and nominate the RASA2–TGFB2–GLI1 axis as a potential therapeutic target in PDAC