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Mechanisms of Hedgehog signaling in glioblastoma

胶质母细胞瘤中 Hedgehog 信号传导机制

基本信息

批准号：
10208542
负责人：
David R Raleigh
金额：
$ 53.45万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10208542
关键词：
Adult Agonist Astrocytes BMP5 gene BMP7 gene Biology Brain CRISPR interference Cancer Etiology Cell membrane Cells Cerebrum Cilia Clinical Data Clinical Trials Coculture Techniques DIF factor Data Defect Development Erinaceidae Extracellular Matrix Gene Activation Gene Expression Gene Targeting Genes Genetic Transcription Glioblastoma Goals Growth Human Ligands Light Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of central nervous system Malignant neoplasm of urinary bladder Modeling Mus Organoids Pathway interactions Patients Pharmacology Process Research Role SHH gene Signaling Protein Structure Surface System Testing Tissue Differentiation Vertebrates Work adult stem cell base bone morphogenic protein cancer cell cancer stem cell cell motility cell type clinically relevant experimental study flexibility human pluripotent stem cell improved in vivo innovation insight live cell imaging migration molecular scale morphogens novel patient derived xenograft model pre-clinical programs single-cell RNA sequencing smoothened signaling pathway stem cell division stem cell homeostasis stem cells targeted treatment transcriptome sequencing tumor tumor growth tumor microenvironment tumor progression tumorigenesis

项目摘要

Project summary Glioblastomas are deadly tumors and account for approximately half of all malignant primary brain cancers. Glioblastoma stem cells exist in interchangeable cellular states that are influenced by the tumor microenvironment, and there is a paucity of information concerning the cellular mechanisms responsible for communicating between glioblastoma cells and the tumor stroma. The Hedgehog pathway, which directs gene expression programs that are essential for development and adult stem cell homeostasis, is critical for survival of glioblastoma stem cells. Paradoxically, a clinical trial suggested that pharmacologic inhibition of the Hedgehog pathway accelerates glioblastoma growth. These clinical data provide an opportunity to re-evaluate how the Hedgehog pathway functions in cancer, and suggest that the role of Hedgehog signaling in glioblastoma stem cells remains to be elucidated. This proposal focuses on understanding how inhibition of the Hedgehog pathway drives glioblastoma at the tumor, cellular, and molecular scale. To do so, our proposal incorporates a novel astrocyte organoid model of glioblastoma that facilitates live imaging of cellular interactions within the tumor microenvironment. When integrated with CRISPR interference, pharmacology, and mouse syngeneic and patient derived xenograft models of glioblastoma, our innovative organoid system will facilitate previously impossible experiments to understand glioblastoma biology. Based on our preliminary organoid, in vivo, and single cell RNA sequencing data presented in this application, we hypothesize that cancer cell-extrinsic Hedgehog signaling in the tumor microenvironment restrains glioblastoma stem cell-renewal and invasion by inducing differentiation factors and remodeling the extracellular matrix. We will test this hypothesis by defining how Hedgehog signals are transduced through the glioblastoma microenvironment; determining if cancer-cell extrinsic Hedgehog signaling restrains glioblastoma stem cells by inducing bone morphogenic protein signaling; and determining if Hedgehog signaling restrains glioblastoma cell invasion by inducing genes that regulate migration through the extracellular matrix. This approached is based on the premise that by studying the mechanisms of Hedgehog signaling in glioblastoma, we will discover new insights into how glioblastoma cells communicate with the tumor microenvironment. Indeed, we know surprisingly little about how interactions between glioblastoma cells and the tumor microenvironment influence cancer progression, and almost nothing about how astrocytes, which comprise the majority of cell types in the adult brain, influence glioblastoma invasion or tumorigenesis. Though the objective of this proposal is to broadly improve our understanding of the mechanisms of Hedgehog signaling in glioblastoma, a long-term goal of this research is to understand these processes well enough to consider targeted therapeutic strategies to improve survival from glioblastoma. Thus, this work will explain why Hedgehog pathway inhibition unexpectedly accelerates glioblastoma growth, elucidate targetable mechanisms, and provide the preclinical basis for new clinical trials in glioblastoma patients.

项目总结