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

• 成果类型: Article
• 署名作者: Li, Jiabo; Shih, Ling - Kai; Markwell, Steven M.; Olson, Cheryl L.; Sullivan, David P.; Arvanitis, Constadina; Ross, James L.; Lam, Nicolas G.; Nuszen, Hannah; Hambardzumyan, Dolores; Becher, Oren J.; Brat, Daniel J.
• 署名单位: Ann & Robert H. Lurie Children's Hospital of Chicago; Robert H. Lurie Comprehensive Cancer Center; Northwestern University; Feinberg School of Medicine; Northwestern University; Feinberg School of Medicine; Emory University; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9009
• DOI: 10.1073/pnas.2416024122
• 发表日期: 2025-02-18
• 关键词: central-nervous-system; pseudopalisading necrosis; cerebral-ischemia; glioblastoma; hypoxia; CLASSIFICATION; expression; pathology; cancer; tumors

摘要

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/flPTENfl/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.