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

Feng Wang, Yang Liu, Wanglong Qiu, Elaine Shum, Monica Feng, Dejian Zhao, Deyou Zheng, Alain Borczuk, Haiying Cheng, Balazs Halmos

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1365-1379
Number of pages15
JournalCancer research
Volume82
Issue number7
DOIs
StatePublished - Apr 1 2022

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Functional Analysis of MET Exon 14 Skipping Alteration in Cancer Invasion and Metastatic Dissemination'. Together they form a unique fingerprint.

Cite this