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; 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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (12)
Jiabo Li
Department of Pathology, Northwestern Medicine Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine
Ling-Kai Shih
Department of Pathology, Northwestern Medicine Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine
Steven M. Markwell
Department of Pathology, Northwestern Medicine Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine
Cheryl L. Olson
Department of Pathology, Northwestern Medicine Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine
David P. Sullivan
Department of Pathology, Northwestern Medicine Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine
Constadina Arvanitis
Department of Cell and Developmental Biology, Northwestern University Feinberg School of Medicine
James L. Ross
Nicolas G. Lam
Department of Pathology, Northwestern Medicine Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine
Hannah Nuszen
Department of Pathology, Northwestern Medicine Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine
Dolores Hambardzumyan
Departments Oncological Sciences and Neurosurgery, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
Oren J. Becher
Jack Martin Division of Pediatric Hematology-Oncology, Mount Sinai Kravis Children’s Hospital, Icahn School of Medicine at Mount Sinai
Daniel J. Brat
Department of Pathology, Northwestern Medicine Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine