Functional Analysis of MET Exon 14 Skipping Alteration in Cancer Invasion and Metastatic Dissemination

MET exon 14 skipping alteration (METD14Ex) is an actionable oncogenic driver that occurs in 2% to 4% of non-small cell lung cancer (NSCLC) cases. The precise role of METD14Ex in tumor progression of NSCLC is poorly understood. Using multiple isogenic METD14Ex cell models established with CRISPR editing, we demonstrate that METD14Ex 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 METD14Ex 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 (MMP) by METD14Ex induced cytoskeleton remodeling and extracellular matrix disassembly, which are critical functional pathways that facilitate cell invasion and metastasis. Therapeutically, MET inhibitors dramatically repressed METD14Ex-mediated tumor growth and metastasis in vivo, indicating potential therapeutic options for METD14Ex-altered NSCLC patients. These mechanistic insights into METD14Ex-mediated invasion and metastasis provide a deeper understanding of the role ofMETD14Ex in NSCLC.