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Principal Investigator: Dionysios C Watson
Organization: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
Fiscal Year: 2024
Award: $249,000
Funding agency: National Cancer Institute
PROJECT SUMMARY: Glioblastoma (GBM) is the most common primary brain tumor and is incurable,
invariably recuring after standard therapy with surgery, chemotherapy and radiation. GBM cell heterogeneity
allows it to thrive in varying adverse conditions in the tumor microenvironment (TME), including therapeutic
insults, hypoxic stress, and immune attack. Interactions with cells in the TME—including neurons, glia,
endothelium, and immune cells—support this heterogeneity and plasticity, contributing to the tumorigenicity,
resistance, and recurrence of this deadly disease. Given the limited efficacy of standard treatment approaches
in GBM, there is an urgent need to decipher and therapeutically target protumorigenic interactions in the TME.
There is evidence that glioma cells form an interconnected network that facilitates the exchange of mitochondria,
which are the main energy-producing organelle and regulate metabolism, proliferation, and epigenetics. There
is also early evidence that mitochondria can be transferred from non-malignant cells to cancer cells. However,
there is limited understanding of mitochondrial transfer dynamics from the TME to GBM; the
mechanisms that govern this transfer; and the downstream effects of transfer on recipient GBM cells.
Addressing this knowledge gap is vital for designing therapeutics that target this interaction. I hypothesize that
mitochondria are transferred from neural cells in the TME to GBM by the action of fusogenic proteins, and that
this transfer drives tumorigenicity by metabolic and epigenetic reprogramming. Specific Aim 1 will test the
hypothesis that astrocytes are the predominant mitochondrial donors, and that transfer is mediated by fusogenic
proteins termed syncytins. I will investigate mitochondrial donor identity using transgenic mice and cell models
expressing lineage-specific mitochondrial fluorophores. I will test how knockdown and overexpression of
syncytins affects rate and protumorigenic effects of transfer from astrocytes to GBM cells. Specific Aim 2 will
test the hypothesis that mitochondrial transfer from astrocytes drives GBM proliferation and tumorigenicity by
metabolic and epigenetic reprogramming. I will investigate how transfer of ATP-synthase with mitochondria
drives tumorigenicity; how mitochondrial transfer results in plasticity of GBM heterogeneity by global metabolic
reprogramming; and how mitochondrial transfer drives proliferation by epigenetic reprogramming and increased
chromatin accessibility. Career development and long-term objectives: I will receive training in cancer
metabolism and brain tumor research, and interact with a mentorship committee of experts from both fields. This
training and the proposed studies are invaluable for my career goal of establishing an independent research
program with the following long-term objectives: (a) elucidate molecular mechanisms of how mitochondrial
transfer reprograms metabolism and epigenetics, (b) develop therapeutics targeting mitochondrial transfer and
its downstream effects, (c) investigate how metabolic interactions in the TME impact other treatment modalities,
including chemotherapy, radiotherapy, and immunotherapy in GBM and other cancers.
Terms: <ATAC sequencing><ATAC-seq><ATACseq><Acetylation><Address><Affect><Assay><Assay for Transposase-Accessible Chromatin using sequencing><Astrocytes><Astrocytus><Astroglia><Automobile Driving><Bioassay><Biological Assay><Biology><Blood leukocyte><Bone Marrow><Bone Marrow Reticuloendothelial System><Brain><Brain Cancer><Brain Neoplasia><Brain Neoplasms><Brain Nervous System><Brain Tumors><Cancers><Cell Body><Cell Cycle><Cell Cycle Genes><Cell Division Cycle><Cell Division Cycle Genes><Cell Growth in Number><Cell Lineage><Cell Multiplication><Cell Proliferation><Cell model><Cells><Cellular Matrix><Cellular Proliferation><Cellular model><Chemotherapy and Radiation><Chemotherapy and/or radiation><Chromatin><Co-culture><Cocultivation><Coculture><Coculture Techniques><Communicating Junction><Complex><Cytoskeletal System><Cytoskeleton><Data><Development><Disease><Disorder><ERVs><Encephalon><Endogenous Retroviruses><Endothelial Cells><Endothelium><Enzyme Gene><Enzymes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Expression Signature><Fellowship><Frequencies><Future><Gap Junctions><Gene Expression><Gene Expression Profile><Genus Hippocampus><Glia><Glial Cell Tumors><Glial Cells><Glial Neoplasm><Glial Tumor><Glioblastoma><Glioma><Goals><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><HERVs><Heterogeneity><Histone Acetylation><Hortega cell><Human><Human Endogenous Retroviruses><Hypoxia><Hypoxic><Immune><Immune mediated therapy><Immunes><Immunodeficient Mouse><Immunologically Directed Therapy><Immunotherapy><In Vitro><Intermediary Metabolism><Knowledge><Kolliker's reticulum><Leukocytes><Leukocytes Reticuloendothelial System><Link><Low-resistance Junction><M Phase><Macrophage><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Brain><Malignant neoplasm of brain><Marrow leukocyte><Mediating><Mediator><Mentorship><Metabolic><Metabolic Processes><Metabolism><Mice><Mice Mammals><Microglia><Mitochondria><Mitochondrial ATP Synthase><Mitochondrial DNA><Mitochondrial F(1)F(0) ATPase><Mitochondrial Proton-Translocating ATPases><Mitosis><Mitosis Stage><Modality><Modeling><Modern Man><Molecular><Morphology><Murine><Mus><Mφ><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neuroglia><Neuroglial Cells><Neuroglial Neoplasm><Neuroglial Tumor><Neurons><Nexus Junction><Non-Malignant><Non-neuronal cell><Nonneuronal cell><Operative Procedures><Operative Surgical Procedures><Organelles><Oxygen Deficiency><PDX model><Pathway interactions><Patient derived xenograft><Patients><Phase><Phenotype><Physicians><Primary Brain Neoplasms><Primary Brain Tumors><Process><Progenitor Cells><Proliferating><Proteins><RNA Seq><RNA sequencing><RNAseq><Radiation therapy><Radiotherapeutics><Radiotherapy><Receptor Protein><Recurrence><Recurrent><Reporter><Research><Research Specimen><Resistance><Role><Scientist><Seahorse><Shapes><Sorting><Specimen><Stress><Supporting Cell><Surgical><Surgical Interventions><Surgical Procedure><Testing><Therapeutic><Training><Transgenic Mice><Tumor Cell><Tumorigenicity><White Blood Cells><White Cell><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><astrocytic glia><brain cell><cancer cell><cancer cell metabolism><cancer metabolism><cancer microenvironment><career><career development><cdc Genes><chemo/radiation therapy><chemotherapy><chemotherapy and radiotherapy><design><designing><developmental><driving><enverin><epigenetically><fluorophore><gene expression pattern><gene expression signature><gene manipulation><genetic manipulation><genetically manipulate><genetically perturb><gitter cell><glial-derived tumor><glioblastoma multiforme><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><in vivo><inhibitor><insight><intracellular skeleton><knock-down><knockdown><malignancy><mesoglia><metabolism measurement><metabolomics><metabonomics><microglial cell><microgliocyte><mitochondrial><mitochondrial based therapeutics><mitochondrial targeted therapeutics><mitochondrial therapeutics><mitotherapeutics><molecular targeted therapeutics><molecular targeted therapies><molecular targeted treatment><mouse model><mtDNA><murine model><neoplasm/cancer><neoplastic cell><nerve cement><neural><neuroglia neoplasm><neuroglia tumor><neuronal><nonmalignant><overexpress><overexpression><pathway><patient derived xenograft model><perivascular glial cell><progenitor><programs><purine/pyrimidine metabolism><radiation or chemotherapy><radiation treatment><receptor><resistance to therapy><resistant><resistant to therapy><scRNA-seq><self-renew><self-renewal><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><spatiotemporal><spongioblastoma multiforme><standard care><standard treatment><stem><stem cells><surgery><syncytin><therapeutic agent development><therapeutic development><therapeutic resistance><therapeutic target><therapy resistant><transcriptional profile><transcriptional signature><transcriptome sequencing><transcriptomic sequencing><treatment resistance><treatment with radiation><tumor><tumor cell metabolism><tumor growth><tumor metabolism><tumor microenvironment><tumors in the brain><white blood cell><white blood corpuscle>