Functional analysis of MET exon 14 skipping alteration in cancer invasion and metastatic dissemination

MET exon 14 skipping alteration (MET∆14Ex) is an actionable oncogenic driver that occurs in 2-4% of non-small cell lung cancer (NSCLC) cases. The precise role of MET∆14Ex in tumor progression of NSCLC is poorly understood. Using multiple isogenic MET∆14Ex cell models established with CRISPR editing, we demonstrate that MET∆14Ex expression increases receptor kinase activity and downstream signaling by impairing receptor internalization and endocytic degradation, significantly boosting cell scatter, migration, and invasion capacity in vitro as well as metastasis in vivo. RNA sequencing analysis revealed that MET∆14Ex preferentially activates biological processes associated with cell movement, providing novel insights into its unique molecular mechanism of action. Activation of PI3K/Akt/Rac1 signaling and upregulation of multiple matrix metallopeptidases (MMPs) by MET∆14Ex induced cytoskeleton remodeling and extracellular matrix disassembly, which are critical functional pathways that facilitate cell invasion and metastasis. Therapeutically, MET inhibitors dramatically repressed MET∆14Ex-mediated tumor growth and metastasis in vivo, indicating potential therapeutic options for MET∆14Ex-altered NSCLC patients. These mechanistic insights into MET∆14Ex-mediated invasion and metastasis provide a deeper understanding of the role of MET∆14Ex in NSCLC.