CD97 maintains tumorigenicity of glioblastoma stem cells via mTORC2 signaling and is targeted by CAR Th9 cells.

Zhou, S; Lin, W; Jin, X; Niu, R; Yuan, Z; Chai, T; Zhang, Q; Guo, M; Kim, SS; Liu, M; Deng, Y; Park, JB; Choi, SI; Shi, B; Yin, J

CD97 maintains tumorigenicity of glioblastoma stem cells via mTORC2 signaling and is targeted by CAR Th9 cells.

Zhou, S Lin, W Jin, X Niu, R Yuan, Z Chai, T Zhang, Q Guo, M Kim, SS Liu, M Deng, Y Park, JB Choi, SI Shi, B

Yin, J

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Publisher:: Elsevier
Publication Type:: Journal Article
Citation:: Cell Rep Med, 2024, 5, (12), pp. 101844
Issue Date:: 2024-12-17

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Field	Value	Language
dc.contributor.author	Zhou, S
dc.contributor.author	Lin, W
dc.contributor.author	Jin, X
dc.contributor.author	Niu, R
dc.contributor.author	Yuan, Z
dc.contributor.author	Chai, T
dc.contributor.author	Zhang, Q
dc.contributor.author	Guo, M
dc.contributor.author	Kim, SS
dc.contributor.author	Liu, M
dc.contributor.author	Deng, Y
dc.contributor.author	Park, JB
dc.contributor.author	Choi, SI
dc.contributor.author	Shi, B https://orcid.org/0000-0002-1043-3163
dc.contributor.author	Yin, J
dc.date.accessioned	2025-01-28T05:20:14Z
dc.date.available	2024-11-06
dc.date.available	2025-01-28T05:20:14Z
dc.date.issued	2024-12-17
dc.identifier.citation	Cell Rep Med, 2024, 5, (12), pp. 101844
dc.identifier.issn	2666-3791
dc.identifier.issn	2666-3791
dc.identifier.uri	http://hdl.handle.net/10453/184303
dc.description.abstract	Glioblastoma (GBM) stem cells (GSCs) contribute to poor prognosis in patients with GBM. Identifying molecular markers is crucial for developing targeted therapies. Here, we identify cluster of differentiation 97 (CD97) as an optimal GSC surface antigen for potential targeting by chimeric antigen receptor (CAR) T cell therapy through in vitro antibody screening. CD97 is consistently expressed in all validated patient-derived GSCs and positively correlated with known intracellular GSC markers. Silencing CD97 reduces GSC tumorigenicity-related activities, including self-renewal, proliferation, and tumor progression. Transcriptome analysis reveals that CD97 activates mTORC2, leading to AKT S473 phosphorylation and enhanced expression of the downstream genes ARHGAP1, BZW1, and BZW2. Inhibiting mTORC2 with JR-AB2-011 suppresses GSC tumorigenicity and downstream gene expression. We develop CD97-CAR T helper (Th) 9 cells, which exhibit potent cytotoxic effects in vitro and extend survival in mice. These findings suggest that CD97 is a promising GSC-enriched antigen and that targeting it with CAR Th9 cells offers a potential therapeutic strategy for GBM.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Elsevier
dc.relation.ispartof	Cell Rep Med
dc.relation.isbasedon	10.1016/j.xcrm.2024.101844
dc.rights	info:eu-repo/semantics/openAccess
dc.subject.classification	32 Biomedical and clinical sciences
dc.subject.mesh	Glioblastoma
dc.subject.mesh	Humans
dc.subject.mesh	Animals
dc.subject.mesh	Neoplastic Stem Cells
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Mice
dc.subject.mesh	Mechanistic Target of Rapamycin Complex 2
dc.subject.mesh	Receptors, Chimeric Antigen
dc.subject.mesh	Antigens, CD
dc.subject.mesh	Carcinogenesis
dc.subject.mesh	Cell Proliferation
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	T-Lymphocytes, Helper-Inducer
dc.subject.mesh	Brain Neoplasms
dc.subject.mesh	Receptors, G-Protein-Coupled
dc.subject.mesh	Mice, Inbred NOD
dc.subject.mesh	Immunotherapy, Adoptive
dc.subject.mesh	Gene Expression Regulation, Neoplastic
dc.subject.mesh	GTPase-Activating Proteins
dc.subject.mesh	Proto-Oncogene Proteins c-akt
dc.subject.mesh	T-Lymphocytes, Helper-Inducer
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Animals
dc.subject.mesh	Mice, Inbred NOD
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Glioblastoma
dc.subject.mesh	Brain Neoplasms
dc.subject.mesh	GTPase-Activating Proteins
dc.subject.mesh	Receptors, G-Protein-Coupled
dc.subject.mesh	Antigens, CD
dc.subject.mesh	Immunotherapy, Adoptive
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Cell Proliferation
dc.subject.mesh	Gene Expression Regulation, Neoplastic
dc.subject.mesh	Proto-Oncogene Proteins c-akt
dc.subject.mesh	Neoplastic Stem Cells
dc.subject.mesh	Carcinogenesis
dc.subject.mesh	Mechanistic Target of Rapamycin Complex 2
dc.subject.mesh	Receptors, Chimeric Antigen
dc.subject.mesh	Glioblastoma
dc.subject.mesh	Humans
dc.subject.mesh	Animals
dc.subject.mesh	Neoplastic Stem Cells
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Mice
dc.subject.mesh	Mechanistic Target of Rapamycin Complex 2
dc.subject.mesh	Receptors, Chimeric Antigen
dc.subject.mesh	Antigens, CD
dc.subject.mesh	Carcinogenesis
dc.subject.mesh	Cell Proliferation
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	T-Lymphocytes, Helper-Inducer
dc.subject.mesh	Brain Neoplasms
dc.subject.mesh	Receptors, G-Protein-Coupled
dc.subject.mesh	Mice, Inbred NOD
dc.subject.mesh	Immunotherapy, Adoptive
dc.subject.mesh	Gene Expression Regulation, Neoplastic
dc.subject.mesh	GTPase-Activating Proteins
dc.subject.mesh	Proto-Oncogene Proteins c-akt
dc.title	CD97 maintains tumorigenicity of glioblastoma stem cells via mTORC2 signaling and is targeted by CAR Th9 cells.
dc.type	Journal Article
utslib.citation.volume	5
utslib.location.activity	United States
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.date.updated	2025-01-28T05:20:10Z
pubs.issue	12
pubs.publication-status	Published
pubs.volume	5
utslib.citation.issue	12

Abstract:

Glioblastoma (GBM) stem cells (GSCs) contribute to poor prognosis in patients with GBM. Identifying molecular markers is crucial for developing targeted therapies. Here, we identify cluster of differentiation 97 (CD97) as an optimal GSC surface antigen for potential targeting by chimeric antigen receptor (CAR) T cell therapy through in vitro antibody screening. CD97 is consistently expressed in all validated patient-derived GSCs and positively correlated with known intracellular GSC markers. Silencing CD97 reduces GSC tumorigenicity-related activities, including self-renewal, proliferation, and tumor progression. Transcriptome analysis reveals that CD97 activates mTORC2, leading to AKT S473 phosphorylation and enhanced expression of the downstream genes ARHGAP1, BZW1, and BZW2. Inhibiting mTORC2 with JR-AB2-011 suppresses GSC tumorigenicity and downstream gene expression. We develop CD97-CAR T helper (Th) 9 cells, which exhibit potent cytotoxic effects in vitro and extend survival in mice. These findings suggest that CD97 is a promising GSC-enriched antigen and that targeting it with CAR Th9 cells offers a potential therapeutic strategy for GBM.

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http://hdl.handle.net/10453/184303