Molecular reprogramming of stromal microarchitecture by tumour-derived extracellular vesicles (EVs) is proposed to favour pre-metastatic niche formation. We elucidated the role of extravesicular tissue inhibitor of matrix metalloproteinase-1 (TIMP1EV) in pro-invasive extracellular matrix (ECM) remodelling of the liver microenvironment to aid tumour progression in colorectal cancer (CRC). Immunohistochemistry analysis revealed a high expression of stromal TIMP1 in the invasion front that was associated with poor progression-free survival in patients with colorectal liver metastases. Molecular analysis identified TIMP1EV enrichment in CRC-EVs as a major factor in the induction of TIMP1 upregulation in recipient fibroblasts. Mechanistically, we proved that EV-mediated TIMP1 upregulation in recipient fibroblasts induced ECM remodelling. This effect was recapitulated by human serum-derived EVs providing strong evidence that CRC release active EVs into the blood circulation of patients for the horizontal transfer of malignant traits to recipient cells. Moreover, EV-associated TIMP1 binds to HSP90AA, a heat-shock protein, and the inhibition of HSP90AA on human-derived serum EVs attenuates TIMP1EV-mediated ECM remodelling, rendering EV-associated TIMP1 a potential therapeutic target. Eventually, in accordance with REMARK guidelines, we demonstrated in three independent cohorts that EV-bound TIMP1 is a robust circulating biomarker for a non-invasive, preoperative risk stratification in patients with colorectal liver metastases.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:91195 |
| Date | 04 June 2024 |
| Creators | Sadananda Rao, Venkatesh, Gu, Qianyu, Tzschentke, Sandra, Lin, Kuailu, Ganig, Nicole, Thepkaysone, May-Linn, Wong, Fang Cheng, Polster, Heike, Seifert, Lena, Seifert, Adrian M., Buck, Nathalie, Riediger, Carina, Weiße, Jonas, Gutschner, Tony, Michen, Susanne, Temme, Achim, Schneider, Martin, Baenke, Franziska, Weitz, Jürgen, Kahlert, Christoph |
| Publisher | Springer Nature |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 1476-5594, 10.1038/s41388-022-02218-9 |
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