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：
10608976
负责人：
David R Raleigh
金额：
$ 52.63万
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/10608976
关键词：
Acceleration Adult Agonist Astrocytes BMP5 gene BMP7 gene Biology Bone Morphogenetic Proteins Brain CRISPR interference Cancer Etiology Cell Communication Cell membrane Cells Cerebrum Cilia Clinical Data Clinical Trials Coculture Techniques Communication DIF factor Data Defect Development Erinaceidae Extracellular Matrix Gene Activation Gene Expression Gene Targeting Genes Genetic Transcription Glioblastoma Goals Growth Human Invaded Ligands 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 antagonist cancer cell cancer stem cell cell motility cell type clinically relevant experimental study flexibility hedgehog signal transduction human pluripotent stem cell improved in vivo innovation insight live cell imaging migration molecular scale morphogens novel patient derived xenograft model pharmacologic pre-clinical programs restraint 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.

项目摘要胶质母细胞瘤是致命的肿瘤，约占所有恶性原发性脑癌的一半。胶质母细胞瘤干细胞存在于受肿瘤影响的可互换细胞状态微环境，并且有关蜂窝机制的信息很少在胶质母细胞瘤细胞和肿瘤基质之间进行通信。指导基因的刺猬途径对发展和成人干细胞稳态至关重要的表达程序对于生存至关重要胶质母细胞瘤干细胞。矛盾的是，一项临床试验表明，药物对刺猬的抑制作用途径加速了胶质母细胞瘤的生长。这些临床数据提供了重新评估的机会刺猬途径在癌症中起作用，并表明刺猬信号在胶质母细胞瘤茎中的作用细胞尚待阐明。该提案重点是了解如何抑制刺猬途径在肿瘤，细胞和分子尺度上驱动胶质母细胞瘤。为此，我们的提议结合了一本小说胶质母细胞瘤的星形胶质细胞器官模型，促进肿瘤内细胞相互作用的现场成像微环境。与CRISPR干扰，药理学和小鼠同性素的整合时我们的创新类器官系统的患者衍生的异种移植模型将促进不可能了解胶质母细胞瘤生物学的实验。基于我们的初步器官，体内和单细胞RNA测序数据在此应用程序中提出，我们假设癌细胞超支肿瘤微环境中的刺猬信号传导限制了胶质母细胞瘤干细胞的更新和侵袭。诱导分化因子并重塑细胞外基质。我们将通过定义来检验这一假设如何通过胶质母细胞瘤微环境转导刺猬信号；确定癌症是否外在的刺猬信号传导通过诱导骨形态发生蛋白信号传导来限制胶质母细胞瘤干细胞。并确定刺猬信号是否通过诱导调节的基因来限制胶质母细胞瘤细胞侵袭通过细胞外基质迁移。这种方法是基于以下前提刺猬信号传导在胶质母细胞瘤中的机制，我们将发现有关胶质母细胞瘤细胞的新见解与肿瘤微环境通信。的确，我们对互动的了解一无所知在胶质母细胞瘤细胞和肿瘤微环境之间会影响癌症的进展，几乎没有任何东西关于成年大脑中大多数细胞类型的星形胶质细胞如何影响胶质母细胞瘤的侵袭或肿瘤发生。尽管该提议的目的是广泛提高我们对胶质母细胞瘤中刺猬信号传导的机制，这项研究的长期目标是了解这些过程足以考虑针对性的治疗策略，以提高胶质母细胞瘤的生存。因此，这项工作将解释为什么刺猬途径抑制出人意料地加速了胶质母细胞瘤的生长，阐明具有目标机制，并为胶质母细胞瘤患者的新临床试验提供了临床前基础。