Dataset Information

Extracellular vesicles from TGF-β-activated cancer-associated fibroblasts remodel the tumor microenvironment through EV surface-associated proteins

ABSTRACT: Cancer-associated fibroblasts (CAFs) are a major stromal cell type within the tumor microenvironment (TME). Transforming growth factor-β (TGF-β) is a key cytokine in the TME that activates CAFs, which alters their ability to remodel the extracellular matrix (ECM) and changes their secretome profile. However, the effects of TGF-β-activated CAF-derived extracellular vesicles (EVs) on the TME, and how TGF-β-induced CAF activation influences the composition of EV cargo and remodels the TME remain largely unexplored. In this study, we reveal the altered protein composition and function of EVs derived from TGF-β-activated CAFs compared to those derived from non-activated CAF-derived EVs. Notably, several proteins that are significantly upregulated in TGF-β-activated CAF-derived EVs (TGF-β-EVs) are found on the surface of these EVs. One such protein is tumor necrosis factor-stimulated gene-6 protein (TSG6), which interacts with its receptor CD44 on the EVs and hyaluronan. These surface-associated proteins facilitate the docking of EVs to cell membrane by binding to transmembrane cell surface receptors. The elevated TSG6 on EV surface promotes the clustering of the co-receptor CD44, and TGF-β type I receptor (TGFBR1) on recipient cells, and thereby enhancing TGF-β receptor signaling. Consequently, TGF-β-EVs further activate CAFs and contribute to the immunosuppression of CD8+ T cells, which facilitates cancer progression. Overall, our findings reveal the effect of CAF-derived EVs on other cell types in TME in a contact-dependent manner, and suggest a potential universal mechanism by which EV surface-associated proteins regulate cell signaling by interacting with and clustering cell receptors, particularly in cells with low EV uptake.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Rayman Tjokrodirijo

LAB HEAD: Peter A. van Veelen

PROVIDER: PXD061656 | Pride | 2026-02-23

REPOSITORIES: Pride

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Publications

Surface-Associated Proteins on Extracellular Vesicles Remodel the Tumor Microenvironment by Potentiating TGF-β Signaling in a Contact-Dependent Manner.

Li Chao C Enciso-Martinez Agustin A Zhu Lizhe L Rotman Sarah A SA van Veelen Peter A PA Koning Roman I RI Mei Hailiang H Ten Dijke Peter P

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20251130 8

Cancer-associated fibroblasts (CAFs) are a major stromal cell type within the tumor microenvironment (TME), where they drive extracellular matrix remodeling and influence tumor progression through the secretion of bioactive molecules. Transforming growth factor-β (TGF-β) is a key regulator of CAF activation, yet its impact on the composition and function of extracellular vesicles (EVs) secreted by CAFs remains largely unexplored. Here, it is shown that TGF-β activation alters the protein cargo a ...[more]

PMID: 41319267

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Project description:Introduction: Oral squamous cell carcinoma (OSCC) is the most common form of head and neck cancer and has a survival rate of ~50% over five years. New treatment strategies are sorely needed to improve survival rates – and a better understanding of the mechanisms underlying tumorigenesis is needed to develop these strategies. The role of the tumor microenvironment (TME) has increasingly been identified as crucial in tumor progression and metastasis. One of the main constituents of the TME, cancer-associated fibroblasts (CAFs), plays a key role in influencing the biological behavior of tumors. Multiple mechanisms contribute to CAF activation, such as TGFβ signaling, but the role of extracellular vesicles (EVs) in CAF activation in OSCC is poorly understood. Assessing the impact of oral cancer-derived EVs on CAF activation will help to better illuminate OSCC pathophysiology and may drive development of novel treatments options. Materials and Methods: EVs were isolated from OSCC cell lines (Cal 27, SCC-9, SCC-25) using differential centrifugation. Nanoparticle tracking analysis was used for EV quantification and size characterization, and Western blot to confirm the presence of EV protein markers. Oral fibroblasts were co-cultured with enriched EVs, TGFβ, or PBS over 72 hours to assess activation. Flow cytometry was used to evaluate the difference in CAF markers. RNA collected from fibroblasts was extracted and the transcriptome was sequenced. Conditioned media from the co-cultures was evaluated with cytokine array profiling. Results: OSCC-derived EVs can activate oral fibroblasts into CAFs that are different from those activated by TGFβ, suggesting different mechanisms of activation and different functional properties. Gene set enrichment analysis using expression data from activated CAFs showed several upregulated inflammatory pathways in those CAFs exposed to OSCC-derived EVs. Marker genes for inflammatory CAF subtypes were also upregulated. This was not seen in CAFs activated by TGFβ. Finally, cytokine array analysis on secreted proteins from CAFs revealed elevated levels of several pro-inflammatory cytokines from CAFs activated by EVs, for instance IL-8 and CXCL5. Conclusions: Taken together, our results reveal the ability of OSCC-derived EVs to activate fibroblasts into CAFs. These CAFs seem to have unique properties, differing from TGFβ-activated CAFs. Gaining an understanding of the interplay between EVs and stromal cells such as CAFs could lead to further insights into OSCC tumorigenesis and potential novel therapeutics.

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