Tumor-secreted extracellular vesicles counteract therapy response by triggering inflammatory mesenchymal stem cell development

The bone marrow is a supportive environment for local or disseminated cancer cells protecting them from the most advanced treatments. Recent observations suggest a critical role for functionally unique 'inflammatory' mesenchymal stem cells (iMSCs) that reside in the bone marrow stroma, yet their origin and function remain largely unknown. Here we show that cancer cell-secreted extracellular vesicles (EVs), known to drive tumor-stroma interactions, induce the development of pro-tumorigenic iMSCs. EV-induced iMSCs recapitulate the single-cell transcriptome of iMSCs in multiple myeloma (MM) and osteosarcoma patient biopsies. Administration of iMSCs secreting high levels of IL6 and IL8 in osteosarcoma-bearing mice promotes lung metastasis formation and counteracts the efficacy of anti-metastatic drugs. Notably, simultaneous blockade of IL8 and IL6 receptors overcomes iMSC-induced drug resistance and reduces tumor burden in both xenograft and immunocompetent models. Mechanistically, cancer EVs act through two distinct mechanisms, EV-bound TGFb induces iMSC IL6 production, while EV-RNA cargo triggers chemokine production by stimulating TLR3 antiviral responses. Our observations establish cancer EVs as physiological triggers of tumor-promoting iMSCs, and iMSCs as major contributors to drug resistance in bone cancer.