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  • About of human primary melanomas

    2021-09-09

    About 67% of human primary melanomas and 56% of melanoma metastases display cytoplasmic or nuclear β-catenin accumulation (Xue et al., 2016). Of note, active β-catenin stimulates emergence of metastasizing melanoma in mice harboring BrafV600E or NrasQ61K hyperplasia (Damsky et al., 2011, Delmas et al., 2007, Gallagher et al., 2013). In several cancers, β-catenin activity is maintained mostly through genetic aberrations affecting β-catenin itself or the β-catenin destruction complex member APC (Zhan et al., 2017). Although a few melanomas harbor somatic CTNNB1 mutations (Xue et al., 2016), in most melanomas the sources of elevated β-catenin activity are unknown. In this study, we uncovered a mechanism of β-catenin induction that is independent of genetic alterations, but relies on PRC2 activity and suppression of the primary cilium. Interestingly, enhanced PRC2 activity also propagates glioblastoma stem cells and initiates dysplasia formation from breast epithelium (Kim et al., 2013, Li et al., 2009). Moreover, in cells of the CNS and the mammary gland, depletion of cilia genes stimulates canonical WNT signaling (Oh and Katsanis, 2013), which is crucial for the formation of glioblastoma and breast cancer, respectively (Lee et al., 2016, Yu et al., 2016). Thus, the mechanism of primary cilium disruption discovered here could maintain oncogenic WNT/β-catenin signaling not only in a large portion of human melanomas but also in tumors of Eptifibatide and breast. Contrary to cutaneous melanoma, malignant peripheral nerve sheath tumors (MPNSTs) harbor LoF mutations abolishing PRC2 activity (De Raedt et al., 2014). Whether these tumors are ciliated is unknown. However, MPNSTs show a signature of elevated SHH signaling (Lévy et al., 2004), a pathway that strongly relies on the primary cilium (Goetz and Anderson, 2010). Likewise, emergence of basal cell carcinoma and medulloblastoma is dependent on both oncogenic SHH signaling and functional cilia (Han et al., 2009, Wong et al., 2009). Of note, Ezh2 deletion in a mouse model of medulloblastoma accelerates tumorigenesis (Vo et al., 2017). Upon disassembly of primary cilia via EZH2, we observed abrogated SHH signaling, whereas WNT signaling was enhanced. Interestingly, SHH-WNT antagonisms are required for neural tube morphogenesis as much as epidermal stem cell expansion (Ouspenskaia et al., 2016, Ulloa and Briscoe, 2007), while the primary cilium counteractively controls these two signaling pathways (Goetz and Anderson, 2010, Oh and Katsanis, 2013). Taken together, acquiring either gain or loss of PRC2 might allow cancers to manipulate the primary cilium, thus ultimately skewing the SHH-WNT interplay toward the preferential oncogenic signaling pathway. Recent immunotherapeutic advancements have resulted in remarkable clinical responses in some melanoma patients. However, the remaining patients frequently acquire resistance to immunotherapies (Sharma et al., 2017). Distinctive mechanisms in suppressing anti-tumor immunity involve tumor-intrinsic PRC2 activity as well as WNT/β-catenin signaling (Spranger et al., 2015, Zingg et al., 2017). Moreover, physical contact between cytotoxic T cells and tumor cells depends on the formation of the cytolytic synapse. Assembly of that structure involves many of the proteins required for primary ciliogenesis (de la Roche et al., 2016). In principle, EZH2 could therefore foster immune escape by suppressing cytolytic synapses or primary cilium formation, the latter potentially increasing immunosuppressive WNT signaling. Several EZH2 inhibitors have entered clinical trials (Kim and Roberts, 2016). Thus, EZH2-targeting might conceivably be considered as a strategy for treating melanoma, possibly in combination with immunotherapies.
    STAR★Methods
    Acknowledgments We thank M. van den Broek, the Flow Cytometry Facility, and the Functional Genomics Center Zurich (University of Zurich) for experimental support. We thank F. Beermann (EPFL, Switzerland), H. Koseki (RIKEN Center for Integrative Medical Sciences, Japan), and M. Eptifibatide Serrano (Centro Nacional de Investigaciones Oncologicas, Spain) for providing Tyr::NrasQ61K, Ezh2lox, and Cdkn2a mice. We thank A. Melnick (Weill Cornell Medical College, USA) and M. T. McCabe (GlaxoSmithKline, USA) for providing EZH2 plasmids and GSK503. This work was funded by the Swiss National Science Foundation (to R.S., 31003A_173056, and L.S., 31003A_169859), including a Sinergia grant (to K.B. and L.S., CRSII3_154412), the Swiss Cancer League (to R.S., KFS-3497-08-2014, and L.S., KFS-3682-08-2015), the Zurich Cancer League (to R.S.), the Zurich University Research Priority Program “Translational Cancer Research” (to K.B., R.D., M.P.L., and L.S.), and the Helmut Horten Foundation (to L.S.).