A clinically relevant model and method to study necrosis as a driving force in glioma restructuring and progression

Jiabo Li; Ling Kai Shih; Steven M. Markwell; Cheryl L. Olson; David P. Sullivan; Constadina Arvanitis; James L. Ross; Nicolas G. Lam; Hannah Nuszen; Dolores Hambardzumyan; Oren J. Becher; Daniel J. Brat

doi:10.1073/pnas.2416024122

A clinically relevant model and method to study necrosis as a driving force in glioma restructuring and progression

Jiabo Li, Ling Kai Shih, Steven M. Markwell, Cheryl L. Olson, David P. Sullivan, Constadina Arvanitis, James L. Ross, Nicolas G. Lam, Hannah Nuszen, Dolores Hambardzumyan, Oren J. Becher, Daniel J. Brat^*

^*Corresponding author for this work

Cell & Developmental Biology

Research output: Contribution to journal › Article › peer-review

Abstract

All glioblastoma (GBM) molecular subsets share the common trait of accelerated progression following necrosis, which cannot be adequately explained by cellular proliferation arising from accumulated genetic alterations. Counter to dogma that “cancer outgrows its blood supply,” we suggest that development of necrosis is not merely a consequence of aggressive neoplastic growth but could be a contributing force causing tumor microenvironment (TME) restructuring and biologic progression. Mechanisms related to necrotic contributions are poorly understood due to a lack of methods to study necrosis as a primary variable. To reveal spatiotemporal changes related to necrosis directly, we developed a mouse model and methodology designed to induce clinically relevant thrombotic vaso-occlusion within GBMs in an immunocompetent RCAS/tv-a mouse model to study TME restructuring by intravital microscopy and demonstrate its impact on glioma progression. Diffuse high-grade gliomas are generated by introducing RCAS-PDGFB-RFP and RCAS-Cre in a Nestin/tv-a; TP53^fl/fl PTEN^fl/fl background mouse. We then photoactivate Rose Bengal in specific, targeted blood vessels within the glioma to induce thrombosis, hypoxia, and necrosis. Following induced necrosis, GBMs undergo rapid TME restructuring and radial expansion, with immunosuppressive bone marrow–derived, tumor-associated macrophages (TAMs) and glioma stem cells (GSCs) increasing dramatically in the perinecrotic niche. Collectively, this model introduces necrosis as the primary variable and captures glioma TME and growth dynamics in a manner that will facilitate therapeutic development to antagonize these mechanisms of progression.

Original language	English (US)
Article number	e2416024122
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	122
Issue number	7
DOIs	https://doi.org/10.1073/pnas.2416024122
State	Published - Feb 19 2025

Funding

This work was supported by NIH/NCI awards R01CA247905 (D.J.B.), R01CA214928 (D.J.B), R21AG086751 (D.P.S.) and P50CA221747 (SPORE for Translational Approaches to Brain Cancer). Microscopy was performed at the Northwestern University Center for Advanced Microscopy, and histology services were provided by the Northwestern University Research Mouse Histology and Phenotyping Laboratory generously supported by NCI CCSG P30CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. Multiphoton microscopy was performed on a Nikon A1R multiphoton microscope, acquired through the support of NIH 1S10OD010398-01. This work was supported by the Small Animal Imaging Division of the CTI at Northwestern University.

Keywords

glioblastoma
glioma stem cell
mouse model
necrosis
tumor-associated macrophage

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Li, J., Shih, L. K., Markwell, S. M., Olson, C. L., Sullivan, D. P., Arvanitis, C., Ross, J. L., Lam, N. G., Nuszen, H., Hambardzumyan, D., Becher, O. J., & Brat, D. J. (2025). A clinically relevant model and method to study necrosis as a driving force in glioma restructuring and progression. Proceedings of the National Academy of Sciences of the United States of America, 122(7), Article e2416024122. https://doi.org/10.1073/pnas.2416024122

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title = "A clinically relevant model and method to study necrosis as a driving force in glioma restructuring and progression",

abstract = "All glioblastoma (GBM) molecular subsets share the common trait of accelerated progression following necrosis, which cannot be adequately explained by cellular proliferation arising from accumulated genetic alterations. Counter to dogma that “cancer outgrows its blood supply,” we suggest that development of necrosis is not merely a consequence of aggressive neoplastic growth but could be a contributing force causing tumor microenvironment (TME) restructuring and biologic progression. Mechanisms related to necrotic contributions are poorly understood due to a lack of methods to study necrosis as a primary variable. To reveal spatiotemporal changes related to necrosis directly, we developed a mouse model and methodology designed to induce clinically relevant thrombotic vaso-occlusion within GBMs in an immunocompetent RCAS/tv-a mouse model to study TME restructuring by intravital microscopy and demonstrate its impact on glioma progression. Diffuse high-grade gliomas are generated by introducing RCAS-PDGFB-RFP and RCAS-Cre in a Nestin/tv-a; TP53fl/fl PTENfl/fl background mouse. We then photoactivate Rose Bengal in specific, targeted blood vessels within the glioma to induce thrombosis, hypoxia, and necrosis. Following induced necrosis, GBMs undergo rapid TME restructuring and radial expansion, with immunosuppressive bone marrow–derived, tumor-associated macrophages (TAMs) and glioma stem cells (GSCs) increasing dramatically in the perinecrotic niche. Collectively, this model introduces necrosis as the primary variable and captures glioma TME and growth dynamics in a manner that will facilitate therapeutic development to antagonize these mechanisms of progression.",

keywords = "glioblastoma, glioma stem cell, mouse model, necrosis, tumor-associated macrophage",

author = "Jiabo Li and Shih, {Ling Kai} and Markwell, {Steven M.} and Olson, {Cheryl L.} and Sullivan, {David P.} and Constadina Arvanitis and Ross, {James L.} and Lam, {Nicolas G.} and Hannah Nuszen and Dolores Hambardzumyan and Becher, {Oren J.} and Brat, {Daniel J.}",

note = "Publisher Copyright: Copyright {\textcopyright} 2025 the Author(s).",

year = "2025",

month = feb,

day = "19",

doi = "10.1073/pnas.2416024122",

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Li, J, Shih, LK, Markwell, SM, Olson, CL, Sullivan, DP , Arvanitis, C, Ross, JL, Lam, NG, Nuszen, H, Hambardzumyan, D, Becher, OJ & Brat, DJ 2025, 'A clinically relevant model and method to study necrosis as a driving force in glioma restructuring and progression', Proceedings of the National Academy of Sciences of the United States of America, vol. 122, no. 7, e2416024122. https://doi.org/10.1073/pnas.2416024122

TY - JOUR

T1 - A clinically relevant model and method to study necrosis as a driving force in glioma restructuring and progression

AU - Li, Jiabo

AU - Shih, Ling Kai

AU - Markwell, Steven M.

AU - Olson, Cheryl L.

AU - Sullivan, David P.

AU - Arvanitis, Constadina

AU - Ross, James L.

AU - Lam, Nicolas G.

AU - Nuszen, Hannah

AU - Hambardzumyan, Dolores

AU - Becher, Oren J.

AU - Brat, Daniel J.

PY - 2025/2/19

Y1 - 2025/2/19

N2 - All glioblastoma (GBM) molecular subsets share the common trait of accelerated progression following necrosis, which cannot be adequately explained by cellular proliferation arising from accumulated genetic alterations. Counter to dogma that “cancer outgrows its blood supply,” we suggest that development of necrosis is not merely a consequence of aggressive neoplastic growth but could be a contributing force causing tumor microenvironment (TME) restructuring and biologic progression. Mechanisms related to necrotic contributions are poorly understood due to a lack of methods to study necrosis as a primary variable. To reveal spatiotemporal changes related to necrosis directly, we developed a mouse model and methodology designed to induce clinically relevant thrombotic vaso-occlusion within GBMs in an immunocompetent RCAS/tv-a mouse model to study TME restructuring by intravital microscopy and demonstrate its impact on glioma progression. Diffuse high-grade gliomas are generated by introducing RCAS-PDGFB-RFP and RCAS-Cre in a Nestin/tv-a; TP53fl/fl PTENfl/fl background mouse. We then photoactivate Rose Bengal in specific, targeted blood vessels within the glioma to induce thrombosis, hypoxia, and necrosis. Following induced necrosis, GBMs undergo rapid TME restructuring and radial expansion, with immunosuppressive bone marrow–derived, tumor-associated macrophages (TAMs) and glioma stem cells (GSCs) increasing dramatically in the perinecrotic niche. Collectively, this model introduces necrosis as the primary variable and captures glioma TME and growth dynamics in a manner that will facilitate therapeutic development to antagonize these mechanisms of progression.

AB - All glioblastoma (GBM) molecular subsets share the common trait of accelerated progression following necrosis, which cannot be adequately explained by cellular proliferation arising from accumulated genetic alterations. Counter to dogma that “cancer outgrows its blood supply,” we suggest that development of necrosis is not merely a consequence of aggressive neoplastic growth but could be a contributing force causing tumor microenvironment (TME) restructuring and biologic progression. Mechanisms related to necrotic contributions are poorly understood due to a lack of methods to study necrosis as a primary variable. To reveal spatiotemporal changes related to necrosis directly, we developed a mouse model and methodology designed to induce clinically relevant thrombotic vaso-occlusion within GBMs in an immunocompetent RCAS/tv-a mouse model to study TME restructuring by intravital microscopy and demonstrate its impact on glioma progression. Diffuse high-grade gliomas are generated by introducing RCAS-PDGFB-RFP and RCAS-Cre in a Nestin/tv-a; TP53fl/fl PTENfl/fl background mouse. We then photoactivate Rose Bengal in specific, targeted blood vessels within the glioma to induce thrombosis, hypoxia, and necrosis. Following induced necrosis, GBMs undergo rapid TME restructuring and radial expansion, with immunosuppressive bone marrow–derived, tumor-associated macrophages (TAMs) and glioma stem cells (GSCs) increasing dramatically in the perinecrotic niche. Collectively, this model introduces necrosis as the primary variable and captures glioma TME and growth dynamics in a manner that will facilitate therapeutic development to antagonize these mechanisms of progression.

KW - glioblastoma

KW - glioma stem cell

KW - mouse model

KW - necrosis

KW - tumor-associated macrophage

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JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

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A clinically relevant model and method to study necrosis as a driving force in glioma restructuring and progression

Abstract

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Keywords

ASJC Scopus subject areas

UN SDGs

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