Cellular plasticity contributes to intra-tumoral heterogeneity and phenotype switching, which enable adaptation to metastatic microenvironments and resistance to therapies. Mechanisms underlying tumor cell plasticity remain poorly understood. SOX10, a neural crest lineage transcription factor, is heterogeneously expressed in melanomas. Loss of SOX10 reduces proliferation, leads to invasive properties, including the expression of mesenchymal genes and extracellular matrix, and promotes tolerance to BRAF and/or MEK inhibitors. We identify the class of cellular inhibitor of apoptosis protein-1/2 (cIAP1/2) inhibitors as inducing cell death selectively in SOX10-deficient cells. Targeted therapy selects for SOX10 knockout cells underscoring their drug tolerant properties. Combining cIAP1/2 inhibitor with BRAF/MEK inhibitors delays the onset of acquired resistance in melanomas in vivo. These data suggest that SOX10 mediates phenotypic switching in cutaneous melanoma to produce a targeted inhibitor tolerant state that is likely a prelude to the acquisition of resistance. Furthermore, we provide a therapeutic strategy to selectively eliminate SOX10-deficient cells.

The results of a prospective phase II trial suggest that radioembolization is a safe and effective first- or second-line treatment for uveal melanoma hepatic metastases. Background Overall survival (OS) for patients with uveal melanoma (UM) hepatic metastases is extremely poor. Therefore, stabilization of hepatic metastases is essential to prolonging OS. Purpose To...

Developmental factors may regulate the expression of immune modulatory proteins in cancer, linking embryonic development and cancer cell immune evasion. This is particularly relevant in melanoma because immune checkpoint inhibitors are commonly used in the clinic. SRY-box transcription factor 10 (SOX10) mediates neural crest development and is required for melanoma cell growth. In this study, we investigate immune-related targets of SOX10 and observe positive regulation of herpesvirus entry mediator (HVEM) and carcinoembryonic-antigen cell-adhesion molecule 1 (CEACAM1). Sox10 knockout reduces tumor growth in vivo, and this effect is exacerbated in immune-competent models. Modulation of CEACAM1 expression but not HVEM elicits modest effects on tumor growth. Importantly, Sox10 knockout effects on tumor growth are dependent, in part, on CD8+ T cells. Extending this analysis to samples from patients with cutaneous melanoma, we observe a negative correlation with SOX10 and immune-related pathways. These data demonstrate a role for SOX10 in regulating immune checkpoint protein expression and anti-tumor immunity in melanoma.

There is no FDA-approved treatment for metastatic uveal melanoma (UM) and overall outcomes are generally poor for those who develop liver metastasis. We performed a retrospective single-institution chart review on consecutive series of UM patients with liver metastasis who were treated at Thomas Jefferson University Hospital between 1971–1993 (Cohort 1, n = 80), 1998–2007 (Cohort 2, n = 198), and 2008–2017 (Cohort 3, n = 452). In total, 70% of patients in Cohort 1 received only systemic therapies as their treatment modality for liver metastasis, while 98% of patients in Cohort 2 and Cohort 3 received liver-directed treatment either alone or with systemic therapy. Median Mets-to-Death OS was shortest in Cohort 1 (5.3 months, 95% CI: 4.2–7.0), longer in Cohort 2 (13.6 months, 95% CI: 12.2–16.6) and longest in Cohort 3 (17.8 months, 95% CI: 16.6–19.4). Median Eye Tx-to-Death OS was shortest in Cohort 1 (40.8 months, 95% CI: 37.1–56.9), and similar in Cohort 2 (62.6 months, 95% CI: 54.6–71.5) and Cohort 3 (59.4 months, 95% CI: 56.2–64.7). It is speculated that this could be due to the shift of treatment modalities from DTIC-based chemotherapy to liver-directed therapies. Combination of liver-directed and newly developed systemic treatments may further improve the survival of these patients.