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  • Landscape of surfaceome and endocytome in human glioma is divergent and depends on cellular spatial organization.

Landscape of surfaceome and endocytome in human glioma is divergent and depends on cellular spatial organization.

Proceedings of the National Academy of Sciences of the United States of America (2022-02-27)
Valeria Governa, Hugo Talbot, Kelin Gonçalves de Oliveira, Myriam Cerezo-Magaña, Anna Bång-Rudenstam, Maria C Johansson, Ann-Sofie Månsson, Karin Forsberg-Nilsson, György Marko-Varga, Julio Enríquez Pérez, Anna Darabi, Johan Malmström, Johan Bengzon, Charlotte Welinder, Mattias Belting
ABSTRACT

Therapeutic strategies directed at the tumor surfaceome (TS), including checkpoint inhibitor blocking antibodies, antibody drug conjugates (ADCs), and chimeric antigen receptor T (CAR-T) cells, provide a new armament to fight cancer. However, a remaining bottleneck is the lack of strategies to comprehensively interrogate patient tumors for potential TS targets. Here, we have developed a platform (tumor surfaceome mapping [TS-MAP]) integrated with a newly curated TS classifier (SURFME) that allows profiling of primary 3D cultures and intact patient glioma tumors with preserved tissue architecture. Moreover, TS-MAP specifically identifies proteins capable of endocytosis as tractable targets for ADCs and other modalities requiring toxic payload internalization. In high-grade gliomas that remain among the most aggressive forms of cancer, we show that cellular spatial organization (2D vs. 3D) fundamentally transforms the surfaceome and endocytome (e.g., integrins, proteoglycans, semaphorins, and cancer stem cell markers) with general implications for target screening approaches, as exemplified by an ADC targeting EGFR. The TS-MAP platform was further applied to profile the surfaceome and endocytome landscape in a cohort of freshly resected gliomas. We found a highly diverse TS repertoire between patient tumors, not directly associated with grade and histology, which highlights the need for individualized approaches. Our data provide additional layers of understanding fundamental to the future development of immunotherapy strategies, as well as procedures for proteomics-based target identification and selection. The TS-MAP platform should be widely applicable in efforts aiming at a better understanding of how to harness the TS for personalized immunotherapy.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Laminin from Engelbreth-Holm-Swarm murine sarcoma basement membrane, 1-2 mg/mL in Tris-buffered saline, 0.2 μm filtered, BioReagent, suitable for cell culture
Roche
cOmplete, Mini Protease Inhibitor Cocktail, Tablets provided in EASYpacks