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Decoding of the surfaceome and endocytome in primary glioblastoma cells identifies potential target antigens in the hypoxic tumor niche

de Oliveira, Kelin Gonçalves LU ; Bång-Rudenstam, Anna LU orcid ; Beyer, Sarah LU ; Boukredine, Axel LU ; Talbot, Hugo LU ; Governa, Valeria LU ; Johansson, Maria C LU ; Månsson, Ann-Sofie LU ; Forsberg-Nilsson, Karin and Bengzon, Johan LU , et al. (2024) In Acta Neuropathologica Communications 12(1).
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Adult, Humans, Glioblastoma/pathology, Brain Neoplasms/pathology, Hypoxia/metabolism, Cell Line, Tumor, Gene Expression Profiling, Membrane Proteins, Tumor Microenvironment
in
Acta Neuropathologica Communications
volume
12
issue
1
article number
35
publisher
BioMed Central (BMC)
external identifiers
  • scopus:85186226954
  • pmid:38414005
ISSN
2051-5960
DOI
10.1186/s40478-024-01740-z
language
English
LU publication?
yes
additional info
© 2024. The Author(s).
id
9a9c15e0-0419-4a70-b56e-7de18e30cea9
date added to LUP
2024-03-07 08:35:14
date last changed
2024-04-20 00:00:59
@article{9a9c15e0-0419-4a70-b56e-7de18e30cea9,
  abstract     = {{<p>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.</p>}},
  author       = {{de Oliveira, Kelin Gonçalves and Bång-Rudenstam, Anna and Beyer, Sarah and Boukredine, Axel and Talbot, Hugo and Governa, Valeria and Johansson, Maria C and Månsson, Ann-Sofie and Forsberg-Nilsson, Karin and Bengzon, Johan and Malmström, Johan and Welinder, Charlotte and Belting, Mattias}},
  issn         = {{2051-5960}},
  keywords     = {{Adult; Humans; Glioblastoma/pathology; Brain Neoplasms/pathology; Hypoxia/metabolism; Cell Line, Tumor; Gene Expression Profiling; Membrane Proteins; Tumor Microenvironment}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Acta Neuropathologica Communications}},
  title        = {{Decoding of the surfaceome and endocytome in primary glioblastoma cells identifies potential target antigens in the hypoxic tumor niche}},
  url          = {{http://dx.doi.org/10.1186/s40478-024-01740-z}},
  doi          = {{10.1186/s40478-024-01740-z}},
  volume       = {{12}},
  year         = {{2024}},
}