Abou-Hamad, John2024-04-192024-04-192024-04-19http://hdl.handle.net/10393/46112https://doi.org/10.20381/ruor-30274SOX9 and SOX10 have both pro-and anti-tumourigenic functions. In melanoma, SOX9 and SOX10 expression are mutually exclusive, suggesting they play unique roles. Here we assessed the role of SOX9 and SOX10 on therapy resistance in BRAF V600E-driven melanoma. We used a panel of syngeneic murine YUMM (Yale University Murine Melanoma) cell lines and demonstrated that these YUMM cells indeed have mutually exclusive expression of SOX9 and SOX10, correlated with their vemurafenib resistance (a BRAFV600E inhibitor). Unexpectedly, exogenous expression of SOX9 or SOX10 did not alter resistance to vemurafenib. Interestingly, SOX9 knockout cells that underwent a vemurafenib treatment regimen didn’t transition to a resistant state and remained sensitive. Sox9 gene activation and Sox10 repression during the transition to the resistant state were in part due to chromatin remodeling. To further explore the role of SOX10 in resistance, we treated vemurafenib resistant YUMM lines with the oncolytic virus VSVΔ51, an emerging therapy. We showed that these resistant cells were also resistant to oncolytic virotherapy. Furthermore, loss of SOX10 recapitulates both the vemurafenib and the oncolytic resistant state in melanoma. SOX10 deletion resulted in an upregulation of various interferon stimulated genes which could play key roles in this cross resistant state. To gain further insights into the role of SOX10 in melanoma, we generated Sox10 knock-out YUMM lines. We found that the loss of SOX10 alters tumour growth by two distinct mechanisms. The loss of SOX10 induces cancer stem cell-like (CSC) properties and lead to a downregulation of CEACAM1, an inhibitory immune receptor found on both immune and cancer cells. This SOX10-CEACAM1 axis led to a decrease in anti-tumour CD8+ T cell infiltration in melanoma tumours. Taken together, we find that SOX9 plays a gatekeeper role during the transition to a targeted therapy resistant state while SOX10 enhances immune evasion and the differentiated state.enAttribution-NonCommercial 4.0 Internationalhttp://creativecommons.org/licenses/by-nc/4.0/MelanomaSOX9SOX10Therapy resistanceThesis