CD147 Mediates the Metabolic Reprogramming of Cancer Associated Fibroblasts Induced by EVs Released by Differentiating Cancer Stem Cells

CD147 Mediates the Metabolic Reprogramming of Cancer Associated Fibroblasts Induced by EVs Released by Differentiating Cancer Stem Cells

ABSTRACT Several reports have demonstrated that CD147, an N‐glycosylated protein that is exchanged by cells in soluble form or through small extracellular vesicles (sEVs), can promote cancer progression. However, its activity related to EVs in colorectal cancer (CRC) is still not fully understood. P...

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Main Authors: Filomena Colella, Federica Calapà, Giulia Artemi, Erica Pazzaglia, Rita Colonna, Sara Vitale, Giacomo Lazzarino, Federica Vincenzoni, Micol Eleonora Fiori, Ruggero De Maria, Sara Lucchisani, Giannicola Genovese, Luigi Perelli, Barbara Tavazzi, Alessandro Sgambato, Donatella Lucchetti
Format: Article
Language:English
Published: Wiley 2025-03-01
Series:Journal of Extracellular Biology
Subjects:
cancer‐associated fibroblasts
CD147
extracellular vesicles
tumour microenvironment
Online Access:https://doi.org/10.1002/jex2.70039
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Summary:ABSTRACT Several reports have demonstrated that CD147, an N‐glycosylated protein that is exchanged by cells in soluble form or through small extracellular vesicles (sEVs), can promote cancer progression. However, its activity related to EVs in colorectal cancer (CRC) is still not fully understood. Previously, we showed that sEV secretion during CRC stem cell (CR‐CSCs) differentiation is partially controlled by CD147, and that CD147‐expressing sEVs (sEVs‐CD147) activate a signalling cascade in recipient cells, inducing molecular invasive features in CR‐CSCs. In the present study, we demonstrated that sEVs‐CD147 increase the expression of myofibroblast and activation markers in cancer‐associated fibroblasts (CAF). In sEVs‐CD147‐activated CAF, aerobic glycolysis was also triggered by the β‐catenin signalling pathway and induced lactate release. These effects were associated with NFKβ upregulation and NO secretion that caused increased cytokines production and VEGF release, respectively. Furthermore, co‐culture with CAF promoted CR‐CSC invasivity in vitro and tumour growth in vivo. Spatial proteomics analysis confirmed in vivo the activation of fibroblasts and the modulation of their metabolic features, within their biological context, after their conditioning with CD147‐expressing sEVs. Our findings indicate that sEV‐packaged CD147 is involved in CAF activation, thus promoting tumour progression via stroma metabolism modification.
ISSN:2768-2811

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