Abstract Triple-negative breast cancer (TNBC) remains one of the most lethal breast cancer subtypes, driven by high metastatic potential and pro-angiogenic tumor-stroma crosstalk, in which extracellular vesicles (EVs) act as critical mediators. CD90 (Thy-1), a GPI-anchored protein linked to cytoskeletal remodeling and invasion, has not been previously explored as a regulator of EV-dependent communication in TNBC biology. Here, we describe a fundamental role for CD90 in controlling the structural integrity, molecular composition, and pro-angiogenic functionality of TNBC-derived EVs. CD90 knockdown in Hs578T TNBC cells impaired angiogenic signaling and motility, disrupting actin architecture and downregulating VEGFA, PDGFRB, and TGF-β. EVs released by CD90-silenced cells (shCD90-EVs) displayed larger and heterogeneous size distribution (203 nm vs 159nm, p = 0.0054) and reduced tetraspanins (CD63, CD9) expression. Functionally, shCD90-EVs (70µg of total protein, approximately 4x109 particles) lost the capacity to promote endothelial and fibroblast migration/invasion and, instead, triggered endothelial disorganization and pronounced cell death in spheroid assays. Ultrastructural analyses revealed tight cellular adhesion, vacuolation, and impaired vesicular dynamics in endothelial cells exposed to shCD90-EVs, in contrast to the membrane remodeling and multivesicular body activity induced by WT-EVs. In ex vivo Chorioallantoic Membrane (CAM) Assay, shCD90-EVs markedly suppressed vasculogenesis, generating thin, irregular, ECM-deficient vessels with altered Collagens I/III/IV and MMP expression. Together, these findings identify CD90 as a previously unrecognized regulator of EV communication in TNBC, integrating cytoskeletal control, angiogenic signaling, and tumor-stroma communication. By demonstrating that CD90 expression dictates whether EVs support or disrupt vascular remodeling, this work positions the CD90-EV axis as a promising therapeutic alternative target to inhibit angiogenesis and metastatic progression in TNBC. Furthermore, the CD90-dependent EV signature emerges as a potential circulating biomarker of TNBC aggressiveness. These findings establish a conceptual and mechanistic foundation for targeting CD90-regulated EV pathways in TNBC translational strategies. Citation Format: Leticia Alves Fernandes, Ana C. Carreira. CD90 knockdown alters extracellular vesicles-mediated communication driving angiogenesis and tumor-stroma crosstalk in triple-negative breast cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3357.
Fernandes et al. (Fri,) studied this question.
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