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Principal Investigator: Pedro R. Lowenstein
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2024
Award: $489,027
Funding agency: National Institute of Neurological Disorders and Stroke
Abstract
Malignant gliomas continue to be the most aggressive and lethal of all brain tumors. In spite of improvements in
surgery, radiotherapy, and chemotherapy, median survival remains ~18-24 months. Gliomas are infiltrative
tumors that invade the surrounding normal brain tissue making total surgical resection impossible. Tumor cells
that remain after surgery eventually lead to tumor recurrence, causing the demise of the patients. Collagen
plays an important role in the progression of various tumors such as breast, prostate and pancreatic tumors. Its
role in gliomas, however, remains poorly understood. Cellular, molecular and functional preliminary data have
identified Collagen1A1 (Col1A1) as an important determinant of tumor progression and invasion. An important
role of Col1A1 in patient survival is supported by the analysis of TCGA, and GLASS, data from human primary
and recurrent gliomas that indicate that median survival is inversely correlated with levels of Col1A1. Human
and experimental mouse gliomas contain fascicles of elongated mesenchymal-like tumor cells that represent
areas of collective motion within the tumor invasive border, and the tumor core; an increase in the density of
these areas is associated with worse prognosis in preclinical mouse models and in human patients. scRNAseq
followed by RNAscope identified two types of cells that express significant levels of Col1A1. High Col1A1-
expressing cells are found within perivascular stroma cells, and glioma cells themselves express lower, but
significant levels of Col1A1. Using laser-microdissection of the mesenchymal-like structures followed by
RNAseq we confirmed that areas of collective motion are enriched in mesenchymal markers such as Col1A1
and ACTA2. These experiments predict an important role for Col1A1 in tumor progression. This was examined
by expressing a shRNA for Col1A1 during the induction of genetically engineered mouse models of glioma
(GEMMs) using our Sleeping Beauty system. Indeed, knockdown of Col1A1 from tumor cells from incipient
GEMMs increased median survival and eliminated areas of fascicles of elongated mesenchymal-like tumor
cells; however, tumors still progressed, animals became moribund, and perivascular expression of Col1A1
remained. This raises the possibility that expression of Col1A1 in perivascular stromal cells plays an important
role in glioma progression. What is not known is if Col1A1 depletion from either tumor or perivascular stromal
cells within established tumors will delay tumor progression and reduce collective motion. Thus, there is a
critical need for a mechanistic understanding of how Col1A1 contributes to glioma progression and invasion.
Our overall objectives are to establish the role of each cellular compartment that expresses Col1A1 on glioma
growth and invasion (AIM 1), the functional role of Col1A1 expression in either cellular compartment on glioma
dynamics (AIM 2), and the role of collagen and its receptors on the response of gliomas to radiation (AIM 3).
Our central hypothesis is that Col1A1 expressing cells play a significant role in glioma progression and
invasion and that blocking Col1A1 and/or its receptors could uncover a novel therapeutic target for GBM.
Terms: <Abscission><Adventitial Cell><Animals><Area><Blood Vessels><Brain><Brain Neoplasia><Brain Neoplasms><Brain Nervous System><Brain Tumors><Breast Neoplasms><Breast Tumors><CAK gene><COL1A1><COL1A1 gene><Cell Adhesion Kinase><Cell Body><Cell Communication and Signaling><Cell Compartmentation><Cell Compartmentations><Cell Signaling><Cells><Collagen><Collagen Fiber><Collagen Receptors><DDR gene><DDR1><DDR1 gene><Data><Discoidin Domain Receptor Family Member 1><EDDR1><Encephalon><Epithelial Discoidin Domain Receptor 1><Epithelial-Specific Receptor Kinase><Excision><Extirpation><Fascicle><GEM model><GEMM model><Gene Deletion><Generalized Growth><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><Growth><Human><Immune><Immunes><Intracellular Communication and Signaling><Invaded><Laser Electromagnetic><Laser Radiation><Lasers><Lesion><Malignant Glial Neoplasm><Malignant Glial Tumor><Malignant Glioma><Malignant Neuroglial Neoplasm><Malignant Neuroglial Tumor><Mammary Cancer><Mammary Neoplasms><Mediating><Mesenchymal><Mice><Mice Mammals><Microdissection><Modeling><Modern Man><Molecular><Motion><Mouse Homolog of PTK3><Murine><Mus><NEP gene><NTRK4><Neuroepithelial Tyrosine Kinase><Neuroglial Neoplasm><Neuroglial Tumor><Neurotrophic Tyrosine Kinase Receptor Type 4><Operative Procedures><Operative Surgical Procedures><Outcome><PTK3 Homolog><Pancreas Neoplasms><Pancreas Tumor><Pancreatic Tumor><Patients><Pattern><Pericapillary Cell><Pericytes><Perivascular Cell><Play><Prognosis><Prostate Neoplasms><Prostate Tumor><Prostatic Neoplasia><Prostatic Neoplasms><RNA Seq><RNA sequencing><RNAseq><RTK6><Radiation><Radiation therapy><Radiotherapeutics><Radiotherapy><Receptor Protein><Receptor Tyrosine Kinase 6><Recurrence><Recurrent><Recurrent Neoplasm><Recurrent tumor><Removal><Role><Rouget Cells><Signal Transduction><Signal Transduction Systems><Signaling><Sleeping Beauty><Stromal Cells><Structure><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><System><TCGA><TRKE><Temodal><Temodar><The Cancer Genome Atlas><Tissue Growth><Transgenic Organisms><Tumor Cell><Tumor Cell Invasion><Tumor Invasion><Tyrosine Kinase Receptor E><biological signal transduction><brain tissue><cancer microenvironment><cancer progression><cell stroma><cell type><chemotherapy><density><evidence base><experiment><experimental research><experimental study><experiments><gene deletion mutation><genetically engineered mouse model><genetically engineered murine model><glial-derived tumor><glioblastoma multiforme><human data><immune microenvironment><immunosuppressive microenvironment><immunosuppressive tumor microenvironment><improved><in vivo><inhibitor><knock-down><knockdown><mammary tumor><methazolastone><mouse model><murine model><neoplasm progression><neoplasm recurrence><neoplastic cell><neoplastic progression><neuroglia neoplasm><neuroglia tumor><neuropathologic><neuropathological><neuropathology><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><ontogeny><pancreatic neoplasia><pancreatic neoplasm><pharmacologic><pre-clinical><preclinical><preservation><radiation treatment><receptor><resection><resistance mechanism><resistant mechanism><response><scRNA-seq><shRNA><short hairpin RNA><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><small hairpin RNA><social role><spongioblastoma multiforme><standard of care><surgery><temozolomide><therapeutic target><transcriptome sequencing><transcriptomic sequencing><transgenic><treatment with radiation><tumor><tumor immune microenvironment><tumor microenvironment><tumor progression><tumor-immune system interactions><tumors in the brain><vascular>