The Hypoxic Tumor Microenvironment Promotes Invadopodia Formation and Metastasis through LPA1 Receptor and EGFR Cooperation
Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels le récepteur des acides lysophosphatiques LPA1 augmente la capacité des cellules cancéreuses à produire des invadopodes dans un environnement hypoxique et, en lien avec le récepteur EGFR, favorise le processus métastatique
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 (LPA4) signaling axis mediates production of the degradative subcellular structures invadopodia, which are known to be required for metastasis. Here, it is demonstrated that LPA1 (LPAR1) is a common and major receptor used for hypoxia-induced invadopodia production in various cancer cell lines. The widespread use of LPA1 was not due to increased LPA1 expression but rather relied on Src-mediated crosstalk with EGFR. LPA1-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 LPA1 inhibition synergistically suppressed metastasis in vivo. Implications: This study uncovers a LPA1-EGFR signaling axis that is used for cell invasion in hypoxia and suggest a potential target to impede cancer metastasis.