Studies of Replication Repair Deficient Brain Tumorigenesis Using Mouse Modeling

Replication repair deficiency (RRD) is a pan-cancer mechanism caused by germline and/or somatically acquired deficiency in the replication repair machinery – DNA polymerase proofreading and the mismatch repair (MMR) system. Germline monoallelic (Lynch Syndrome, LS) or biallelic (Constitutional Mismatch Repair Deficiency, CMMRD) mutations in MMR genes, are present in 5-10% of glioblastomas in children, adolescents, and young adults. RRD brain tumors are characterized by universal hypermutation, resistance to standard chemoradiation, and variable susceptibility to immune-based therapies. Despite their clinical relevance, representative immunocompetent models of recently defined RRD subgroups are lacking. These subgroups are identified by specific somatically acquired mutations, survival, and immunotherapy response. MMR-deficiency (MMRD) in combination with polymerase proofreading deficiency (PPD) define MMRD+PPD tumors, while those lacking PPD are associated with recurrent TP53 mutations representing MMRD-only tumors. Using germline mutations and brain development-specific Cre-drivers, we genetically engineered MMRD+PPD and MMRD-only mouse models that faithfully recapitulate the tumor spectrum and genomic characteristics of each human RRD subgroup. All mouse models robustly developed brain tumors displaying phenotypic variation. Using a trans-species approach, we elucidated a mechanistic model of RRD-driven brain tumorigenesis. We revealed that the cell-of-origin significantly contributes to determining brain tumor type, location, and age of tumor onset in mouse models, suggesting a strong impact of early- or late-RRD mutational onset for patient tumor biology. Specifically, the differences in germline mutagenesis onset between CMMRD and LS patients directly impacts timeline of brain tumor formation and survival. We further demonstrate the dynamic interplay between POLE mutations and MMRD status in modulating the likelihood of brain tumorigenesis. To extend the understanding of the interaction between hypermutation and the immune system in RRD subgroups, the tumor immune microenvironment (TIME) was characterized in spontaneously forming brain tumors in each model. Subgroup-specific immune infiltration patterns were identified, highlighting an important role for CD8+ T cell modulation in controlling brain tumor growth, suggesting an underlying mechanism that may inform therapeutic strategies in RRD patients. Collectively, this doctoral thesis advances our understanding of RRD-driven brain tumorigenesis, optimization of subgroup-tailored immunotherapy approaches, and putative surveillance protocols. These novel models provide a valuable pre-clinical platform to elucidate RRD tumor biology in vivo.

Department dc:contributor.department

Medical Science

Year dc:date.issued

2025

Author dc:creator

• Aamir, Zoya

Advisor dc:contributor.advisor

• Tabori, Uri UT

• Animal Modeling
• Brain Tumors
• Cancer Genetics
• Immunotherapy
• Replication Repair Deficiency

Handle dc:identifier.uri

https://hdl.handle.net/1807/150624

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/150624