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Principal Investigator: Yi Fan
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $386,788
Funding agency: National Institute of Neurological Disorders and Stroke
Project Summary
Glioblastoma (GBM), the grade IV glioma, is among the most lethal of human malignancies, distinguished
by prominent vascularity. GBM is the most aggressive primary brain tumor with a current median survival of
about 14-16 months, largely due to its high resistance to conventional cytotoxic therapies. Overgrown
vasculature characterizes the tumor microenvironment that fuels GBM progression and induces vascular
niche-mediated therapeutic resistance. However, current anti-vascular therapy that primarily targets pro-
angiogenic factors including VEGF, albeit initially groundbreaking, has encountered major difficulties and
failures in treating most malignant solid tumors including GBM, likely due to insufficient eradication or
functional inhibition of tumor-associated endothelial cells (ECs). Our recent studies suggest that EC
plasticity by genetic reprogramming is a driving force that induces EC resistance to anti-angiogenic and
cytotoxic treatments. Here, our preliminary study by single-cell transcriptome analysis of tumor-associated
ECs reveals that ECs acquire mesenchymal and stemness-like gene signature in a genetically engineered
mouse GBM model. Utilizing human specimens and EC lineage-tracing systems, our studies reveal robust
treatment resistance in GBM-associated ECs. Our in vitro and in vivo data suggest that genetic reprogramming
into mesenchymal stem cell (MSC)-like cells induces EC chemoresistance through Wnt activation in GBM.
Therefore, we hypothesize that mesenchymal and stemness-like genetic reprogramming in tumor ECs
induces therapy resistance in GBM. We will test this hypothesis by pursuing the following aims: 1) Define
the molecular mechanism underlying EC plasticity and treatment resistance with a focus on Wnt activation;
2) Determine the in vivo role of c-Met/Wnt-mediated EC plasticity in tumor progression; and 3) Test
experimental therapy that combines EC plasticity inhibition with radio/chemotherapy or anti-angiogenic
therapy in orthotopic mouse GBM models. Successful completion of the proposed work will provide novel
insights into tumor microenvironment-dependent treatment resistance, and may lead to development of a
new therapeutic strategy by targeting endothelial plasticity in cancer.
Terms: <Angiogenesis Antagonists><Angiogenesis Blockers><Angiogenesis Factor><Angiogenesis Inhibitors><Angiogenetic Antagonists><Angiogenetic Inhibitors><Angiogenic Antagonists><Angiogenic Factor><Angiogenic Inhibitors><Angiostatic Agents><Anti-Angiogenetic Agents><Anti-Angiogenic Agents><Anti-Angiogenic Drugs><Anti-VEGF><Anti-VEGF Humanized Monoclonal Antibody><Anti-VEGF RhuMAb><Antiangiogenesis Agents><Antiangiogenic Agents><Antiangiogenic Drugs><Area><Beta Cadherin-Associated Protein><Beta-1 Catenin><Blood Vessels><C10 chemokine><CUL-2><Cancer Treatment><Cancers><Cell Body><Cell Communication and Signaling><Cell Growth in Number><Cell Lineage><Cell Locomotion><Cell Migration><Cell Movement><Cell Multiplication><Cell Proliferation><Cell Signaling><Cell Therapy><Cells><Cellular Migration><Cellular Motility><Cellular Proliferation><Chemoresistance><Chemotherapy and Radiation><Chemotherapy and/or radiation><Combined Modality Therapy><Cytotoxic Chemotherapy><Cytotoxic Therapy><Data><Development><Dysfunction><Embryo Development><Embryogenesis><Embryonic Development><Endothelial Cells><Endothelium><Experimental Therapies><FLK1><Failure><Fibroblasts><Fibrosis in the heart><Fibrosis in the myocardium><Fibrosis within the heart><Fibrosis within the myocardium><Fibrotic myocardium><Functional disorder><GEM model><GEMM model><Genes><Genetic><Genetically Engineered Mouse><Glial Cell Tumors><Glial Neoplasm><Glial Tumor><Glioblastoma><Glioma><Goals><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><Grant><Human><In Vitro><Inflammatory Muscle Diseases><Inflammatory Myopathy><Intracellular Communication and Signaling><Investigational Therapies><Investigational Treatments><KDR gene><KO mice><Kaposi Sarcoma><Kaposi's Sarcoma><Knock-out Mice><Knockout Mice><Liver Fibrosis><MIP-related protein 1><MRP-1><Malignant><Malignant - descriptor><Malignant Melanoma><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Mediating><Melanoma><Mesenchymal><Mesenchymal Progenitor Cell><Mesenchymal Stem Cells><Mesenchymal progenitor><Mesenchymal stromal/stem cells><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><MoAb VEGF><Modeling><Modern Man><Molecular><Monitor><Monoclonal Antibody Anti-VEGF><Multimodal Therapy><Multimodal Treatment><Multiple Hemorrhagic Sarcoma><Murine><Mus><Myositis><Neoplasm Metastasis><Neovascularization Inhibitors><Neuroglial Neoplasm><Neuroglial Tumor><Null Mouse><Nutrient><O element><O2 element><Oncogenesis><Oxygen><PRO2286><Pathologic><Phenotype><Phosphorylation><Physiologic Ossification><Physiological Ossification><Physiopathology><Play><Primary Brain Neoplasms><Primary Brain Tumors><Protein Phosphorylation><RNA Seq><RNA sequencing><RNAseq><Radio><Recombinant Humanized Anti-VEGF Monoclonal Antibody><Recombinant Humanized Monoclonal Antibody to Vascular Endothelial Growth Factor><Refractory><Research Specimen><Resistance><RhuMAb VEGF><Role><Science><Secondary Neoplasm><Secondary Tumor><Signal Transduction><Signal Transduction Systems><Signaling><Solid Neoplasm><Solid Tumor><Specimen><Stem Cell like><System><Temodal><Temodar><Testing><Therapeutic><Therapeutic Effect><VEGF><VEGF Receptors><VEGFR><VEGFR-2><VEGFR2><VEGFs><VPF Receptor><Vascular Endothelial Cell Growth Factor Receptor><Vascular Endothelial Growth Factor Receptor 2><Vascular Endothelial Growth Factors><Vascular Permeability Factor Receptor><Vascularization><Work><angiogenesis><anti-cancer therapy><antiangiogenic><beta catenin><bevacizumab><biological signal transduction><cancer metastasis><cancer microenvironment><cancer progression><cancer therapy><cancer-directed therapy><cardiac fibrosis><cell mediated therapies><cell motility><cell-based therapeutic><cell-based therapy><cellular therapeutic><cellular therapy><chemo/radiation therapy><chemoresistant><chemotherapy><chemotherapy and radiotherapy><chemotherapy resistance><chemotherapy resistant><combination therapy><combined modality treatment><combined treatment><coronary fibrosis><cytotoxic><developmental><driving force><experimental therapeutic agents><experimental therapeutics><fibrotic heart><fibrotic liver><gene signatures><genetic signature><genetically engineered mouse model><genetically engineered murine model><glial-derived tumor><glioblastoma multiforme><global gene expression><global transcription profile><heart fibrosis><hepatic fibrosis><in vivo><insight><kidney fibrosis><knock-down><knockdown><macrophage inflammatory protein-related protein-1><malignancy><mesenchymal stromal progenitor cells><mesenchymal-derived stem cells><methazolastone><mouse model><multi-modal therapy><multi-modal treatment><murine model><myocardial fibrosis><neoplasm progression><neoplasm/cancer><neoplastic progression><neuroglia neoplasm><neuroglia tumor><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><normal ossification><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><ossification><paracrine><pathophysiology><pharmacologic><pre-clinical><preclinical><progenitor-like cell><radiation or chemotherapy><renal fibrosis><resistance to therapy><resistant><resistant to therapy><response><rhuMabVEGF><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><spongioblastoma multiforme><stem cell characteristics><stem-like cell><stemness><temozolomide><therapeutic resistance><therapy resistant><transcriptome><transcriptome sequencing><transcriptomic sequencing><treatment resistance><trend><tumor><tumor cell metastasis><tumor eradication><tumor growth><tumor microenvironment><tumor progression><tumorigenesis><vascular><vascular abnormality><β-catenin>