Surface proteomics of cancer-derived extracellular vesicles reveals universal heat shock proteins and cancer signatures.

Authors

Leyla Ayse Erozenci, Fenna Feenstra, Sander R Piersma, Thang V Pham, Jianang Liu, Joke Wortel, Jan R T van Weering, Natasja F J Dits, Guido Jenster, R Jeroen A van Moorselaar, Irene V Bijnsdorp, Connie R Jimenez

Published in

Molecular & cellular proteomics : MCP. Pages 101649. Aug 21, 2026. Epub Aug 21, 2026.

Abstract

Extracellular vesicles (EVs) secreted by cancer cells are a valuable source of non-invasive biomarkers, as they are released into biofluids and reflect the molecular makeup of their cells of origin. To enable direct capture and detection of cancer-derived EVs, detailed knowledge of their surface proteome is essential. Here, we combined mild enzymatic treatment with mass spectrometry to analyze outward-facing proteins of EVs across a panel of 18 cell lines. This approach identified 1094 EV-associated surface proteins, including 144 transmembrane proteins involved in cellular communication and transport. Peptide-level analyses revealed that nearly 50% of multi-pass transmembrane proteins, such as ATP1A1, displayed their intracellular domains on the external EV surface. Out of a core set of 112 EV surface proteins shared across all cancer types, we report a top list of 15 highly abundant EV-surface proteins including ATP1A1, heat shock proteins HSPA8 and HSP90AB1 and nuclear proteins linked to EV biogenesis and cancer progression. This comprehensive profiling of EV surface proteomes from diverse cancer types reveals a robust set of pan-cancer EV surface markers with potential for diagnostic analysis. Significance: Over the past decade, EVs have emerged as critical mediators of intercellular communication in both physiological and pathological contexts. While the EV proteome is well-known, detailed knowledge is missing on which proteins are outward facing on the EV surface that would enable to develop tools to isolate cancer-specific EVs. We report a comprehensive EV surface proteome across multiple cancer types, revealing both universally present surface proteins and tumor type-specific markers. A top list of 15 pan-cancer EV surface proteins included heat shock proteins HSPA8 and HSP90AB1 as well as ATP1A1. These findings not only advance our understanding of the molecular architecture of the EV surface but also lay the foundation for developing targeted EV capture strategies for diagnostic and therapeutic applications across diverse cancers.

PMID:
42628842
Bibliographic data and abstract were imported from PubMed on 22 Aug 2026.

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