Data from Functional Analysis of <i>MET</i> Exon 14 Skipping Alteration in Cancer Invasion and Metastatic Dissemination

Abstract

&lt;div&gt;Abstract&lt;p&gt;&lt;i&gt;MET&lt;/i&gt; exon 14 skipping alteration (&lt;i&gt;METΔ14Ex&lt;/i&gt;) is an actionable oncogenic driver that occurs in 2% to 4% of non–small cell lung cancer (NSCLC) cases. The precise role of &lt;i&gt;METΔ14Ex&lt;/i&gt; in tumor progression of NSCLC is poorly understood. Using multiple isogenic &lt;i&gt;METΔ14Ex&lt;/i&gt; 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 &lt;i&gt;in vitro&lt;/i&gt; as well as metastasis &lt;i&gt;in vivo&lt;/i&gt;. RNA sequencing analysis revealed that &lt;i&gt;METΔ14Ex&lt;/i&gt; 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 &lt;i&gt;METΔ14Ex&lt;/i&gt;-mediated tumor growth and metastasis &lt;i&gt;in vivo&lt;/i&gt;, indicating potential therapeutic options for &lt;i&gt;METΔ14Ex&lt;/i&gt;-altered NSCLC patients. These mechanistic insights into &lt;i&gt;METΔ14Ex&lt;/i&gt;-mediated invasion and metastasis provide a deeper understanding of the role of &lt;i&gt;METΔ14Ex&lt;/i&gt; in NSCLC.&lt;/p&gt;Significance:&lt;p&gt;These findings reveal the mechanistic function of &lt;i&gt;METΔ14Ex&lt;/i&gt; alteration in driving metastasis and define novel metastasis-related pathways that could be targeted for more effective treatment of lung cancer with &lt;i&gt;METΔ14Ex&lt;/i&gt; alterations.&lt;/p&gt;&lt;/div&gt;