Cancer stem cells render a complex cascade of events that facilitates highly invasive melanoma malignancy. Interplay between immunocytes and cancer stem cells within tumor microenvironment with the participation of sphingolipid signaling mediators skews the immune evasion strategies toward metastatic neoplasm. In this context, we aimed to explore the functional aspect of glucosylceramide synthase (GCS), a key enzyme of sphingolipid biosynthesis in the maintenance of melanoma stem cell-like cancer cells (CSCs). Our findings demonstrated that tumor hypoxia was responsible for elevated GCS expression in melanoma, which was correlated with substantially increased melanoma CSCs. Moreover, hypoxia-induced TGF-β from TAMs and Tregs promoted GCS induction in B16F10 murine melanoma CSCs via PKCα signaling and facilitated the expansion of melanoma CSCs. Interestingly, GCS ablation hindered the immunosuppressiveness of TAMs and Tregs. Therefore, our study for the first time demonstrated a novel paracrine pathway of melanoma CSC maintenance and tumorigenicity, exploiting the bidirectional signaling with immunocytes. Furthermore, our study showed that the combinatorial immunotherapy involving immunomodulators like Mw and DTA-1 repressed CSC pool affecting GCS functions in advanced-stage B16F10 murine melanoma tumor. Moreover, GCS inhibition sensitized conventional chemotherapeutic drug-resistant melanoma CSCs to the genotoxic drugs paving the way toward selective melanoma treatment. Better therapeutic efficacy with inhibition of GCS and CSC depletion suggests a crucial role of GCS in melanoma treatment, therefore, implying its application concerning clinical challenges of chemotherapy resistance leading to prolonged survival.
Keywords: TGF-β; cancer stem cell; glucosylceramide synthase; hypoxia; melanoma.
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