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  • br Author contributions br Conflict

    2024-06-11


    Author contributions
    Conflict of interest
    Acknowledgements This work was supported by the National Natural Science Foundation of China (81502276), Major Projects of Science and Technology of Health and Family Planning Commission of Hunan Province (A2017013), the Natural Science Foundation of Hunan Province (2016JJ4077), and the Natural Science Foundation of Guangxi (No. 2015GXNSFEA139003).
    Introduction Metastasis is a complex multistep process that involves intra-tumoral cell invasion followed by entry into the circulation (intravasation), and completes when the cancer Methylprednisolone Sodium Succinate sale invade (extravasation) and survive in distant tissues to grow as macro-metastatic lesions (Lambert et al., 2017). Unfortunately, once the disease spreads to secondary organs it becomes virtually incurable (Kedrin et al., 2007). Among breast cancers, both the Triple-Negative (TNBC) and HER2-positive (HER2+) subtypes are linked to poor survival due to their propensity for metastasis (Seal and Chia, 2010, Visvader, 2009). HER2 is a member of the epidermal growth factor receptor (EGFR) of receptor tyrosine kinases (RTKs) that is overexpressed or amplified in ∼20% of human breast cancers and transmits signals mediating tumor growth, invasion, and metastasis (Brenton et al., 2005). While some patients afflicted with HER2+ breast cancer benefit from anti-HER2 therapeutic treatment, others may either be unresponsive or will develop resistance and relapse with a metastatic disease (De Laurentiis et al., 2005, Mukohara, 2011). Hence, defining the molecular mechanisms by which HER2 promotes cancer spreading may reveal novel anti-metastatic therapeutic strategies. AXL, TYRO3, and MER collectively form the TAM family of RTKs. Within this family, AXL is specifically activated by its ligand GAS6 (Graham et al., 2014, Linger et al., 2008, O’Bryan et al., 1991). While TAMs are dispensable for embryonic development, their compound genetic deletions in mice revealed their essential role in inhibiting innate immunity (Lemke and Rothlin, 2008, Rothlin et al., 2007). TAMs are frequently implicated in diseases, and AXL is broadly expressed in solid cancers including breast cancer, non-small cell lung carcinoma, ovarian cancer, and clear cell renal carcinoma where its levels correlate with increased risks of metastasis (Gjerdrum et al., 2010, Lozneanu et al., 2016, Rankin et al., 2010, Shieh et al., 2005, Yu et al., 2015). In addition, AXL expression correlates with the acquisition of mesenchymal features of cancer cells and provides advantages to tumors such as increased invasion and resistance to antimitotic agents in vitro (Asiedu et al., 2014, Gjerdrum et al., 2010, Vuoriluoto et al., 2011, Wilson et al., 2014). Within breast cancer cell lines, AXL expression is restricted to cells with the Triple-Negative gene signature, such that AXL is viewed as a marker of this breast cancer subtype (D’Alfonso et al., 2014, Wilson et al., 2014). Whether AXL is activated by GAS6 during cancer progression and metastasis remains unclear. GAS6 expression correlates with positive outcome in breast cancer (Mc Cormack et al., 2008) while it is linked to increased metastasis in non-small cell lung cancer (Wu et al., 2017). AXL can also bypass Methylprednisolone Sodium Succinate sale the need of GAS6 by cooperating with other transmembrane receptors including EGFR, MET, platelet-derived growth factor (PDGF), and VEGFR-2 (Meyer et al., 2013, Ruan and Kazlauskas, 2012, Salian-Mehta et al., 2013). In this study, we set out to develop murine genetic models of AXL and GAS6 deletion to test their role on metastasis in HER2+ breast cancer. We extended these observations in tumor specimens and human cell lines, including patient-derived xenografts (PDXs), and tested whether pharmacological inhibition of AXL could be a valid strategy to limit breast cancer metastasis.
    Results
    Discussion AXL expression is primarily limited to breast cancer cell lines representative of the triple-negative molecular subtypes, and virtually no expression is detectable in luminal or HER2+ cell lines (D’Alfonso et al., 2014, Wilson et al., 2014). An emerging feature of AXL expression across multiple solid tumor cell lines is the link with EMT (i.e., cells expressing mesenchymal markers) (Antony et al., 2016, Wilson et al., 2014). These data have led to the establishment of AXL as a candidate marker of TNBC. In this study, we demonstrate that AXL is expressed in a subset of HER2+ human breast cancers that display an EMT signature and this is linked to poor clinical outcome. Based on these data, we sought to determine if AXL plays a functional role and if it is an actionable target during HER2+ breast cancer progression. Through a series of genetic and functional assays, we demonstrate a central role for AXL in promoting metastasis in the context of HER2+ breast cancer.