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    • An AXL decoy receptor with enhanced GAS binding properties

    2023-11-01

    An AXL decoy receptor with enhanced GAS6-binding properties, MYD1, was engineered as a therapeutic tool to disrupt GAS6/AXL signaling in vivo (Kariolis et al., 2014). MYD1 was shown to block metastasis of human ovarian cancer Nitrendipine and a murine breast cancer cell line in grafting assays in mice. These data led to the notion that targeting GAS6 might be a novel approach to limit metastasis. In contrast, by using a genetic approach to characterize a pre-clinical breast cancer model, we found that GAS6, but not AXL, was dispensable for HER2-driven metastasis in vivo. These findings not only demonstrate that autocrine secretion of GAS6 from cancer cells is not required for metastasis, but also that GAS6 expressed in the lungs is not acting as a homing factor for the cancer cells in this model. Rather, AXL appears to physically interact with HER2, thereby bypassing the necessity for GAS6, and this leads to HER2-mediated transphosphorylation and activation of AXL that triggers cell invasion. Recent data suggest that AXL heterodimerization with other transmembrane receptors occurs in multiple pathophysiological contexts (Meyer et al., 2013, Ruan and Kazlauskas, 2012, Salian-Mehta et al., 2013). Our results provide mechanistic details demonstrating that the interaction of AXL with HER2 increases both AXL half-life and its localization at the cell surface. Interestingly, the formation of HER2/EGFR heterodimers has also been reported to stabilize EGFR at the cell surface leading to enhanced oncogenic signaling (Hendriks et al., 2003, Lenferink et al., 1998). Hence, ligand-independent activation of AXL could be a common event in cancers driven by RTKs. One implication of our findings is that determining the GAS6-dependency of tumors for metastasis may be important before considering therapeutic approaches that target the GAS6/AXL interaction. Unlike in humans, our murine models have the limitation that metastasis only occurs to lungs, therefore we cannot exclude the possibility that GAS6 could be important in controlling metastasis to other organs. In prostate cancer models, GAS6 expressed by the bone promotes a tumor cell dormancy state (Shiozawa et al., 2010). It will be important to determine if GAS6 is important for bone metastasis because it is a frequent site of dissemination in HER2+ breast cancer patients. In addition, PROTEIN S (PROS1), a GAS6-related protein that preferentially activates TYRO3 and MERTK over AXL (Linger et al., 2008), is also expressed in murine HER2+ tumors. Whether dual targeting of GAS6 and PROS1 would impact AXL-mediated metastasis remains to be tested. The plasticity of EMT is critical to allow for efficient metastasis (Li and Kang, 2016, Aceto et al., 2015). Acquisition of EMT features facilitates migration within the primary tumor and intravasation (Giampieri et al., 2009), prepares the cells in the circulation for extravasation (Labelle et al., 2011), and is required for extravasation (Padua and Massagué, 2009). AXL is frequently expressed in cancer cells of various origins that display mesenchymal features (Gjerdrum et al., 2010, Wu et al., 2014). While there is now substantial evidence to suggest that AXL is a promoter of metastasis in solid cancers, its contributions to the various steps of the metastatic process as an effector of EMT and throughout the metastatic cascade have not been dissected. While HER2+ cancers retain epithelial features, the progression to the metastatic stage is thought to require EMT (Wu et al., 2016). We report here that AXL is essential for the intravasation of HER2+ cancer cells, as measured by quantifying the CTCs in both immune-competent and immune-compromised mice. We confirmed the contribution of AXL to EMT-induced invasion in multiple models, in particular using a human the HER2+ cell line HCC1954 and the HER2+ PDX cell. Interestingly, the HER2+ PDX cells used in this study does not express AXL and mesenchymal markers in basal conditions like other HER2+ breast cancer cell lines studied to date (D’Alfonso et al., 2014, Wilson et al., 2014), unless they are reprogrammed by TGF-β. We also found that AXL is a mediator of TGF-β-induced extravasation of HER2+ cancer cells. Hence, AXL may be needed to allow for efficient TGF-β-reprogramming of cells for extravasation. Our findings that AXL is essential for extravasation in HER2+ cancer cells are in agreement with several experimental metastasis assays that have suggested a role for AXL in the extravasation of triple-negative breast cancer cells (Vuoriluoto et al., 2011). However, the major difference is that triple-negative breast cancer cells are initially mesenchymal and express high AXL while HER2+ cells must undergo EMT for AXL expression and AXL-mediated extravasation.