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Role of Cancer-Associated Fibroblasts in Cholangiocarcinoma

癌症相关成纤维细胞在胆管癌中的作用

基本信息

批准号：
10414782
负责人：
Xin Chen
金额：
$ 60.91万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-19 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10414782
关键词：
Ablation Affect Apoptotic Blocking Antibodies Cell Compartmentation Cell Death Cell Proliferation Cells Characteristics Cholangiocarcinoma Clinical Clinical Research Coculture Techniques Collagen Collagen Receptors Desmoplastic Development Drug usage Extracellular Matrix FDA approved Family Fibroblasts Fibrosis Gene Expression Genes Goals Growth Human In Vitro Incidence Injections Integrins Interruption Intrahepatic Cholangiocarcinoma Knock-out Knockout Mice Light Link Liver Liver neoplasms Malignant Neoplasms Malignant neoplasm of pancreas Measures Mediating Mediator of activation protein Mus Myofibroblast Nature Outcome Pancreas Pathway interactions Pharmaceutical Preparations Pharmacology Platelet-Derived Growth Factor Primary Malignant Neoplasm of Liver Protein Isoforms Role Sampling Signal Pathway Signal Transduction Survival Rate System Testing Therapeutic Time Tumor Promoters Tumor Promotion Tumor-Derived cancer genetics conventional therapy discoidin domain receptor 1 discoidin receptor experimental study genetic approach in vivo inhibiting antibody innovation interest intrahepatic liver injury migration neoplastic cell new therapeutic target nintedanib novel novel therapeutic intervention recruit single cell sequencing single-cell RNA sequencing tool tumor tumor microenvironment

项目摘要

Intrahepatic cholangiocarcinoma (ICC) is an aggressive liver tumor with limited therapeutic options and 5-year survival rates of less than 10%. ICC is characterized by its highly desmoplastic nature, with abundance of cancer- associated fibroblasts (CAF) and extracellular matrix (ECM). The role of CAF and ECM in ICC remain controversial due to the paucity of functional in vivo studies. While the majority of ICC in vitro studies support a cancer-promoting role of CAF, recent studies in endogenously arising pancreatic cancer, a highly desmoplastic tumor with many similarities to ICC, have shown that CAF restrain cancer growth. Here, we seek to answer the question whether CAF promote or restrain ICC, using a number of novel and cell-specific tools to manipulate CAF and tumor cells and their crosstalk in endogenously arising ICC in vivo. We hypothesize that CAF and ECM provide a niche that promotes ICC growth and survival, and that detailed characterization of ICC-CAF crosstalk will identify novel therapeutic targets within the tumor microenvironment. In Aim 1, we will determine the role CAF using novel tools to determine how genetic CAF inhibition or early and late CAF ablation affect ICC growth, proliferative and anti-apoptotic signaling pathways, and mouse survival. In Aim 2, we will investigate pathways that mediate the recruitment, proliferation and activation of CAF in ICC focusing on the hypothesis that tumor cells hijack normal fibrogenic mechanism in the liver via tumor-derived TGFb and PDGF isoforms and TGFb- activating integrins, resulting in accumulation and activation of CAF. In addition to detailed mechanistic studies in knockout mice and in vitro co-cultures, we will determine whether pharmacologic inhibition of CAF activation by FDA-approved drug Nintedanib or integrin-blocking antibodies inhibit ICC growth and prolong mouse survival. In Aim 3, we will determine pathways through which CAF modulate ICC growth, focusing on the hypothesis that CAF-derived ECM activates tumor-promoting signals in the tumor cell compartment. To test this hypothesis, we will investigate ICC development in mice with CAF-specific knockout of Col1a1, or tumor-selective knockout of collagen-sensing receptor discoidin domain receptor 1 (DDR1). In addition, we will determine whether ECM- mediated stiffness and subsequent activation of mechanosensitive signaling in tumor cells promote ICC development. We will measure tumor stiffness, activation of mechanosensitive signaling pathways and DDR1 expression in human CCA samples and correlate these to clinical outcomes. The role of stiffness and DDR1 in ICC growth and CAF-ICC crosstalk will be investigated in more detail in vitro through modulation of stiffness and by co-culturing CAF and ICC cells that lack Col1a1 or DDR1, respectively. In summary, the proposed studies will employ novel tools to answer a long-standing question in the field and may provide a basis for targeting ICC- CAF crosstalk as novel therapeutic strategy for this devastating malignancy.

肝内胆管癌（ICC）是一种侵袭性肝脏肿瘤，治疗选择有限，5年