Radiation induces ESCRT pathway dependent CD44v3+ extracellular vesicle production stimulating pro-tumor fibroblast activity in breast cancer

Abstract

Despite recent advances in radiotherapeutic strategies, acquired resistance remains a major obstacle, leading to tumor recurrence for many patients. Once thought to be a strictly cancer cell intrinsic property, it is becoming increasingly clear that treatment-resistance is driven in part by complex interactions between cancer cells and non-transformed cells of the tumor microenvironment. Herein, we report that radiotherapy induces the production of extracellular vesicles by breast cancer cells capable of stimulating tumor-supporting fibroblast activity, facilitating tumor survival and promoting cancer stem-like cell expansion. This pro-tumor activity was associated with fibroblast production of the paracrine signaling factor IL-6 and was dependent on the expression of the heparan sulfate proteoglycan CD44v3 on the vesicle surface. Enzymatic removal or pharmaceutical inhibition of its heparan sulfate side chains disrupted this tumor-fibroblast crosstalk. Additionally, we show that the radiation-induced production of CD44v3+ vesicles is effectively silenced by blocking the ESCRT pathway using a soluble pharmacological inhibitor of MDA-9/Syntenin/SDCBP PDZ1 domain activity, PDZ1i. This population of vesicles was also detected in the sera of human patients undergoing radiotherapy, therefore representing a potential biomarker for radiation therapy and providing an opportunity for clinical intervention to improve treatment outcomes.

Extracellular Vesicles in Breast Cancer: From Biology and Function to Clinical Diagnosis and Therapeutic Management

“…In a mouse BC model, SEVs derived from irradiated cells elicited immune responses of tumor-specific CD8+ T cells and inhibition of tumor size [ 391 ]. Likewise, radioresistant SEVs stimulate tumor-supporting fibroblast activity, facilitating tumor survival and promoting cancer stem-like cell expansion [ 392 ].…”

Biological Role and Aberrant Overexpression of Syntenin-1 in Cancer: Potential Role as a Biomarker and Therapeutic Target

“…The interaction with TGF-beta has also been associated with the modulation of the GTPase RhoA, Cdc42, and TGFB1 in the EMT of breast cancer [ 88 ]. In breast cancer, the interaction of syntenin-1 with ESCRT promotes the activation of pro-tumoral fibroblast [ 89 ]. Additionally, it can regulate the expression of pEGFR and PBCL2 to inhibit autophagy markers [ 12 ], and its interaction with TGF-β can give place to proliferation in EMT [ 86 ].…”