Abstract 4584: Apoptosis-mediated AXL activation: Contribution to metastatic cancers

Abstract

Abstract AXL is a receptor tyrosine kinase that is widely expressed in a variety of cancers and is predictive of poor patient outcome. This receptor is an essential epithelial-to-mesenchymal transition-induced regulator of cancer metastasis and is related to the occurrence of treatment resistance. AXL activation requires both the lipid moiety phosphatidylserine (PtdSer) and the bridging protein ligand Gas6. PtdSer is only available to mediate AXL activation when it is externalized on cell membranes, an event that occurs specifically during apoptosis. For that reason, we aimed to identify if apoptotic cell debris is capable of activating AXL on cancer cells and how this would affect the metastatic capacity of these cells. In a non-AXL expressing tumor cell line (HCC827) apoptosis was induced by means of UV-irradiation. We detected AXL activation of AXL-expressing MDA-MB-231 cells that were treated with HCC827 cell debris, suggesting that apoptotic debris of dying tumor cells is capable of activating AXL in surviving surrounding tumor cells. Next we determined the contribution of PtdSer-mediated AXL activation to the migration of MDA-MB-231 cells in a wound scratch assay. The addition of warfarin, which prevents autocrine Gas6 binding to PtdSer, decreased migration to a similar extent as the AXL inhibitor R428. This study revealed that PtdSer-mediated AXL activation contributes to the migration properties of MDA-MB-231 cells. As we detected AXL activation upon addition of PtdSer-containing apoptotic cells debris, this suggests that the induction of apoptosis by cancer therapeutics might enhance the metastatic capacities of neighboring surviving tumor cells. This finding may broadly impact the oncology field given AXL's widespread expression among different types of cancers, and provides a rationale for the design of novel combination therapies for decreasing tumor metastasis. Citation Format: Annelien Zweemer, Aaron Meyer, Douglas Lauffenburger. Apoptosis-mediated AXL activation: Contribution to metastatic cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4584.