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Decoding of the surfaceome and endocytome in primary glioblastoma cells identifies potential target antigens in the hypoxic tumor niche
Lund Univ, Dept Clin Sci, Sect Oncol, Barngatan 4, S-22185 Lund, Sweden..
Lund Univ, Dept Clin Sci, Sect Oncol, Barngatan 4, S-22185 Lund, Sweden..ORCID iD: 0000-0003-2706-9502
Lund Univ, Dept Clin Sci, Sect Oncol, Barngatan 4, S-22185 Lund, Sweden..
Lund Univ, Dept Clin Sci, Sect Oncol, Barngatan 4, S-22185 Lund, Sweden..
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2024 (English)In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 12, article id 35Article in journal (Refereed) Published
Abstract [en]

Immunotherapies with antibody-drug-conjugates (ADC) and CAR-T cells, targeted at tumor surface antigens (surfaceome), currently revolutionize clinical oncology. However, target identification warrants a better understanding of the surfaceome and how it is modulated by the tumor microenvironment. Here, we decode the surfaceome and endocytome and its remodeling by hypoxic stress in glioblastoma (GBM), the most common and aggressive brain tumor in adults. We employed a comprehensive approach for global and dynamic profiling of the surfaceome and endocytosed (endocytome) proteins and their regulation by hypoxia in patient-derived GBM cultures. We found a heterogeneous surface-endocytome profile and a divergent response to hypoxia across GBM cultures. We provide a quantitative ranking of more than 600 surface resident and endocytosed proteins, and their regulation by hypoxia, serving as a resource to the cancer research community. As proof-of-concept, the established target antigen CD44 was identified as a commonly and abundantly expressed surface protein with high endocytic activity. Among hypoxia induced proteins, we reveal CXADR, CD47, CD81, BSG, and FXYD6 as potential targets of the stressed GBM niche. We could validate these findings by immunofluorescence analyses in patient tumors and by increased expression in the hypoxic core of GBM spheroids. Selected candidates were finally confronted by treatment studies, showing their high capacity for internalization and ADC delivery. Importantly, we highlight the limited correlation between transcriptomics and proteomics, emphasizing the critical role of membrane protein enrichment strategies and quantitative mass spectrometry. Our findings provide a comprehensive understanding of the surface-endocytome and its remodeling by hypoxia in GBM as a resource for exploration of targets for immunotherapeutic approaches in GBM.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2024. Vol. 12, article id 35
Keywords [en]
Immunotherapy, Glioblastoma, Tumor antigens, Proteomics, Hypoxia
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-525916DOI: 10.1186/s40478-024-01740-zISI: 001174242900001PubMedID: 38414005OAI: oai:DiVA.org:uu-525916DiVA, id: diva2:1848084
Funder
Swedish Cancer SocietyAvailable from: 2024-04-02 Created: 2024-04-02 Last updated: 2024-04-02Bibliographically approved

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Forsberg Nilsson, Karin

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