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

Author:

Wang Feng12,Liu Yang3,Qiu Wanglong4,Shum Elaine5ORCID,Feng Monica12,Zhao Dejian6ORCID,Zheng Deyou3ORCID,Borczuk Alain7,Cheng Haiying12,Halmos Balazs12

Affiliation:

1. Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York.

2. Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York.

3. Department of Genetics, Albert Einstein College of Medicine, Bronx, New York.

4. Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York.

5. Perlmutter Cancer Center, New York University Langone Health, New York, New York.

6. Yale Center for Genome Analysis, Yale University, New Haven, Connecticut.

7. Department of Pathology, Weill Cornell Medicine, New York, New York.

Abstract

Abstract MET exon 14 skipping alteration (METΔ14Ex) is an actionable oncogenic driver that occurs in 2% to 4% of non–small cell lung cancer (NSCLC) cases. The precise role of METΔ14Ex in tumor progression of NSCLC is poorly understood. Using multiple isogenic METΔ14Ex cell models established with CRISPR editing, we demonstrate that METΔ14Ex 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 METΔ14Ex 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 METΔ14Ex induced cytoskeleton remodeling and extracellular matrix disassembly, which are critical functional pathways that facilitate cell invasion and metastasis. Therapeutically, MET inhibitors dramatically repressed METΔ14Ex-mediated tumor growth and metastasis in vivo, indicating potential therapeutic options for METΔ14Ex-altered NSCLC patients. These mechanistic insights into METΔ14Ex-mediated invasion and metastasis provide a deeper understanding of the role of METΔ14Ex in NSCLC. Significance: These findings reveal the mechanistic function of METΔ14Ex alteration in driving metastasis and define novel metastasis-related pathways that could be targeted for more effective treatment of lung cancer with METΔ14Ex alterations.

Funder

HHS | NIH | National Cancer Institute

American Cancer Society

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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