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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：
10058245
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/10058245
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 Immunocompetent 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 Prognosis Publishing Role Solid Neoplasm Starvation Stress Stromal Cells Testing Therapeutic Tissues Transgenic Mice Transgenic Model base cancer cell cell behavior cell type cytokine in vivo inhibition of autophagy innovation insight interest neoplastic cell promoter recruit response therapeutic target tool tumor tumor growth tumor microenvironment tumor progression tumorigenic wound healing

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.

项目总结癌的进展取决于上皮性肿瘤细胞与其周围间质的相互作用。成纤维细胞是这种基质的主要成分，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，许多实体瘤显示出明显的成纤维细胞的组织学证据。增殖和活化，称为结缔组织增生症。尽管结缔组织增生症与人类癌症密切相关预后不佳，产生和维持这种促结缔组织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的自噬对于促进结缔组织发育和肿瘤进展。自噬是一种受到严格控制的溶酶体降解促进肿瘤细胞存活和代谢适应的过程。人们对瞄准目标非常感兴趣由于自噬对肿瘤细胞存活的影响是公认的；然而，潜在的亲肿瘤宿主间质中自噬的致瘤作用尚不清楚。我们假设自噬在间质成纤维细胞是启动和维持促结缔组织增生性纤维化反应和促进肿瘤的关键进步。使用我们独家开发的强大的免疫功能乳腺癌模型和工具实验室，我们将严格审查间质成纤维细胞自噬在癌症进展过程中的功能在活体内。在目标1中，我们将确定基质成纤维细胞的自噬如何调节组织僵硬和细胞外基质。改建。在目标2中，我们将剖析基质成纤维细胞依赖自噬的分泌如何促进癌症的进展和影响肿瘤的微环境。在目标3中，我们将证实间质成纤维细胞自噬在乳腺癌原发肿瘤进展和转移中的作用模特们。这些研究将提供独特的概念性见解，以了解自噬途径是否以及如何在宿主成纤维细胞可以被调节以取消癌症进展所需的间质反应。