Single-cell and spatial transcriptomics reveal mTOR-driven cellular fate of spindle cells and immune evasion in classic Kaposi's sarcoma
Abstract
BACKGROUND: Classic Kaposi's sarcoma (CKS) is an angiogenic tumor with no standardized treatment. Increased mTOR pathway activity in tumors fuels oncogenesis by stimulating anabolic metabolism, cell proliferation, and angiogenesis. This study aimed to assess the therapeutic potential of mTOR inhibitor metformin in CKS patients.
METHODS: Two consecutive patients with biopsy-proven, CKS received metformin as monotherapy, and we further leverage single-cell RNA sequencing and spatial transcriptomics to uncover its underlying molecular mechanisms.
RESULTS: Rapid clinical response with no adverse effects was observed in 2 CKS patients. Further investigation identified characteristic spindle cells (SCs) exhibiting heightened activity in VEGF, mTOR, and hypoxia signaling pathways, suggestive of a terminal stromal differentiation state. Besides, the immune landscape was characterized by a high proportion of CD8+ Tex and NK cells displaying suppressed cytotoxicity and migration functions. Crucially, SCs were found to interact with immune cells predominantly via the CXCL9-CXCR3 signaling axis.
CONCLUSION: This study reveals the mTOR-driven differentiation of SCs in KS pathogenesis aligning with rapid clinical improvement in CKS patients, which provides compelling evidence for metformin's therapeutic potential in CKS.
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