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Stromal Fibroblast Autophagy In Tumor Progression and Desmoplasia

肿瘤进展和结缔组织形成中的基质成纤维细胞自噬

基本信息

批准号：
9472077
负责人：
Jayanta Debnath
金额：
$ 32.89万
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：
2017
资助国家：
美国
起止时间：
2017-12-13 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9472077
关键词：
Affect Angiogenic Factor Animals Autophagocytosis Behavior Biological Biological Assay Breast Cancer Model Carcinoma Cell Proliferation Cell Survival Cell secretion Cells Cellular Metabolic Process Clinical Collagen Collagen Type I Data Deposition Desmoplastic Eating Epithelial Exhibits Exposure to Extracellular Matrix Fibroblasts Fibrosis Genetic Growth Factor Histologic Human Hypoxia Immune Impairment In Vitro Inflammation Invaded Laboratories Lead LoxP-flanked allele Malignant Neoplasms Mammary Neoplasms Metabolic Modeling Molecular Mus Neoplasm Metastasis Nutrient Pathway interactions Peptide Hydrolases Polyomavirus Primary Neoplasm Process Publishing Role Solid Neoplasm Starvation Stress Stromal Cells Testing Therapeutic Tissues Transgenic Mice Transgenic Model Wound Healing base cancer cell cell behavior cell type cytokine in vivo inhibition of autophagy innovation insight interest neoplastic cell outcome forecast promoter recruit response therapeutic target tool tumor tumor growth tumor microenvironment tumor progression tumorigenic

项目摘要

PROJECT SUMMARY Carcinoma progression depends on the interactions of epithelial tumor cells with their surrounding stroma. Fibroblasts represent a principal component of this stroma, which modulates tumor cell behavior through diverse mechanisms, including the synthesis of growth and angiogenic factors, cytokines, extracellular matrix components and proteases. Indeed, many solid tumors exhibit striking histological evidence of fibroblast proliferation and activation, termed desmoplasia. Although desmoplasia in human cancers tightly correlates with poor prognosis, the molecular mechanisms that generate and maintain this desmoplastic response remain unknown. In preliminary studies, we have uncovered that autophagy in stromal fibroblasts is crucial for promoting both desmoplasia and tumor progression. Autophagy is a tightly regulated lysosomal degradation process that promotes tumor cell survival and metabolic adaptation. There is great interest in targeting autophagy against cancer due to its well-established effects on tumor cell survival; however, the potential pro- tumorigenic functions of autophagy in the host stroma remain unknown. We hypothesize that autophagy in stromal fibroblasts is critical to initiate and maintain a desmoplastic fibrotic response and to facilitate tumor progression. Using powerful immune-competent mammary cancer models and tools uniquely developed in our laboratory, we will rigorously scrutinize the functions of stromal fibroblast autophagy during cancer progression in vivo. In Aim 1, we will determine how autophagy in stromal fibroblasts modulates tissue stiffness and ECM remodeling. In Aim 2, we will dissect how autophagy-dependent secretion by stromal fibroblasts promotes carcinoma progression and influences the tumor microenvironment. In Aim 3, we will corroborate the effects of stromal fibroblast autophagy in mammary cancer progression and metastasis using autochthonous tumor models. These studies will provide unique conceptual insight into whether and how the autophagy pathway in host fibroblasts can be modulated to abolish the stromal response required for cancer progression.

项目概要癌症进展取决于上皮肿瘤细胞与其周围基质的相互作用。成纤维细胞是该基质的主要成分，它通过以下方式调节肿瘤细胞的行为：多种机制，包括生长和血管生成因子、细胞因子、细胞外基质的合成成分和蛋白酶。事实上，许多实体瘤表现出成纤维细胞的惊人组织学证据增殖和激活，称为结缔组织增生。尽管人类癌症中的结缔组织增生与如果预后不良，产生和维持这种促纤维增生反应的分子机制仍然存在未知。在初步研究中，我们发现基质成纤维细胞中的自噬对于促进结缔组织增生和肿瘤进展。自噬是一种严格调控的溶酶体降解促进肿瘤细胞存活和代谢适应的过程。对目标有很大兴趣自噬对抗癌症，因为其对肿瘤细胞存活的明确影响；然而，潜在的亲宿主基质中自噬的致瘤功能仍不清楚。我们假设自噬基质成纤维细胞对于启动和维持促结缔组织增生性纤维化反应以及促进肿瘤生长至关重要进展。使用我们独特开发的强大的免疫能力乳腺癌模型和工具实验室，我们将严格审查基质成纤维细胞自噬在癌症进展过程中的功能体内。在目标 1 中，我们将确定基质成纤维细胞中的自噬如何调节组织硬度和 ECM 重塑。在目标 2 中，我们将剖析基质成纤维细胞的自噬依赖性分泌如何促进癌症进展并影响肿瘤微环境。在目标 3 中，我们将验证以下效果：使用原生肿瘤进行乳腺癌进展和转移中的基质成纤维细胞自噬模型。这些研究将为自噬途径是否以及如何参与提供独特的概念见解。可以调节宿主成纤维细胞以消除癌症进展所需的基质反应。