Data from The Hypoxic Tumor Microenvironment Promotes Invadopodia Formation and Metastasis through LPA1 Receptor and EGFR Cooperation

Abstract

<div>Abstract<p>Hypoxia, a common feature of solid tumors, has been critically involved in cell invasion and metastasis, but the underlying mechanisms remain poorly understood. Previously, it has been observed that the lysophosphatidic acid receptor 4 (LPA<sub>4</sub>) signaling axis mediates production of the degradative subcellular structures invadopodia, which are known to be required for metastasis. Here, it is demonstrated that LPA<sub>1</sub> (LPAR1) is a common and major receptor used for hypoxia-induced invadopodia production in various cancer cell lines. The widespread use of LPA<sub>1</sub> was not due to increased LPA<sub>1</sub> expression but rather relied on Src-mediated cross-talk with EGFR. LPA<sub>1</sub>-mediated phosphorylation of Y845-EGFR under hypoxia led to PI3K/Akt activation, an event that increases the ability of cells to produce invadopodia. Moreover, phospho-Y845-EGFR was upregulated in hypoxic zones of tumors and a combination of EGFR and LPA<sub>1</sub> inhibition synergistically suppressed metastasis <i>in vivo</i>.</p><p><b>Implications:</b> This study uncovers an LPA<sub>1</sub>–EGFR signaling axis that is used for cell invasion in hypoxia and suggests a potential target to impede cancer metastasis. <i>Mol Cancer Res; 16(10); 1601–13. ©2018 AACR</i>.</p></div>