Targeting SOX10-deficient cells to reduce the dormant-invasive phenotype state in melanoma

Abstract

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.

Chick cranial neural crest cells release extracellular vesicles that are critical for their migration

“…However, it is unclear whether the use of exosomes to achieve these ends represents a cancer-specific process, hijacking of normal cellular physiology or reuse of a developmental program. Indeed, melanoma cells reactivate neural crest pathways during oncogenesis ( Capparelli et al, 2022 ; Kaufman et al, 2016 ; Rambow et al, 2018 ) and EMT ( Gupta et al, 2005 ). We wondered whether signaling through extracellular vesicles could be another normal NCC mechanism dysregulated by cancer cells.…”

“…Like metastatic cells leaving a solid cancerous tumor, NCCs undergo EMT and migrate away from their site of origin in the dorsal neural tube using related transcriptional, signaling and morphological processes ( Powell et al, 2013 ; Theveneau and Mayor, 2012 ). As a cancer of NCC-derived melanocytes, melanoma cells reactivate the NCC transcriptional program ( Capparelli et al, 2022 ; Kaufman et al, 2016 ; Rambow et al, 2018 ) and follow environmental cues to migrate along NCC pathways ( Bailey et al, 2012 ), suggesting that NCCs migrate and melanoma cells metastasize using shared mechanisms.…”

Anin vivoavian model of human melanoma to perform rapid and robust preclinical studies

“…Hence, the neural crest origin of these melanoma cells may have impacted their ability to integrate microenvironmental signals, which are known to influence NCC migratory and differentiation properties. We then wondered whether exposure of melanoma cells to this particular embryonic microenvironment could have modified the expression of key actors of the SOX10-MITF axis, well described to be involved in melanomagenesis (Capparelli et al , 2022; Shakhova et al , 2015; Cheli et al , 2011). A375P cells are known to display a NCSC-like expression pattern (MITF low , SOX10 + ) as recently analyzed at the single cell level (Wouters et al , 2020).…”

Connecting Metabolic Rewiring With Phenotype Switching in Melanoma

“…Beyond MITF, other melanoma lineage-restricted factors, involved in coordinating metabolism and cell fate have been described. Indeed, the role of the neural crest lineage transcription factor SOX10 has recently emerged (Capparelli et al, 2022). SOX10 is, like MITF, heterogeneously expressed in melanoma (Rambow et al, 2018), and has been proposed as a regulator of phenotype switching in cutaneous melanoma (Capparelli et al, 2022) since its genetic ablation impairs proliferation and promotes the acquisition of invasive features and drug tolerance.…”

“…Indeed, the role of the neural crest lineage transcription factor SOX10 has recently emerged (Capparelli et al, 2022). SOX10 is, like MITF, heterogeneously expressed in melanoma (Rambow et al, 2018), and has been proposed as a regulator of phenotype switching in cutaneous melanoma (Capparelli et al, 2022) since its genetic ablation impairs proliferation and promotes the acquisition of invasive features and drug tolerance. Accordingly, melanoma cells lacking SOX10 display gene enrichment in EMT programs, as well as in metabolism and microenvironment-related pathways such as hypoxia and glycolysis (Capparelli et al, 2022).…”