ABSTRACT
High-grade gliomas (HGG), including glioblastomas, are characterized by invasive growth, resistance to therapy, and high inter- and intra-tumoral heterogeneity. The key histological hallmarks of glioblastoma are pseudopalisading necrosis and microvascular proliferation, which allow pathologists to distinguish glioblastoma from lower-grade gliomas. In addition to being genetically and molecularly heterogeneous, HGG are also heterogeneous with respect to the composition of their microenvironment. The question of whether this microenvironmental heterogeneity is driven by the molecular identity of the tumor remains controversial. However, this question is of utmost importance since microenvironmental, non-neoplastic cells are key components of the most radiotherapy- and chemotherapy-resistant niches of the tumor. Our work demonstrates a versatile, reliable, and reproducible adult HGG mouse model with NF1-silencing as a driver mutation. This model shows significant differences in tumor microenvironment, expression of subtype-specific markers, and response to standard therapy when compared to our established PDGFB-overexpressing HGG mouse model. PDGFB-overexpressing and NF1-silenced murine tumors closely cluster with human proneural and mesenchymal subtypes, as well as PDGFRA-amplified and NF1-deleted/mutant human tumors, respectively, at both the RNA and protein expression levels. These models can be generated in fully immunocompetent mixed or C57BL/6 genetic background mice, and therefore can easily be incorporated into preclinical studies for cancer cell-specific or immune cell-targeting drug discovery studies.
Subject(s)
Brain Neoplasms/pathology , Gene Expression Regulation, Neoplastic/genetics , Glioma/pathology , Mutation/genetics , Proto-Oncogene Proteins c-sis/metabolism , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/genetics , Brain Neoplasms/therapy , Cell Line, Tumor , Cell Proliferation , Cerebral Ventricles/pathology , Dacarbazine/analogs & derivatives , Dacarbazine/pharmacology , Dacarbazine/therapeutic use , Disease Models, Animal , Doublecortin Domain Proteins , Gene Expression Regulation, Neoplastic/drug effects , Glioma/diagnostic imaging , Glioma/genetics , Glioma/therapy , Humans , Hyaluronan Receptors/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Microtubule-Associated Proteins/metabolism , Nestin/genetics , Nestin/metabolism , Neurofibromin 1/genetics , Neurofibromin 1/metabolism , Neuropeptides/metabolism , PTEN Phosphohydrolase/genetics , PTEN Phosphohydrolase/metabolism , RNA, Small Interfering/administration & dosage , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , TemozolomideABSTRACT
The intermolecular enantioselective C-H functionalization with acceptor-only metallocarbenes is reported using a new family of Ir(iii)-bis(imidazolinyl)phenyl catalysts, developed based on the interplay of experimental and computational insights. The reaction is tolerant of a variety of diazoacetate precursors and is found to be heavily influenced by the steric and electronic properties of the substrate. Phthalan and dihydrofuran derivatives are functionalized in good yields and excellent enantioselectivities.