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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：
10166796
负责人：
Xin Chen
金额：
$ 62.16万
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 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10166796
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 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.

肝内胆管细胞癌(ICC)是一种侵袭性较强的肝脏和肿瘤患者，其治疗方案选择有限，为期5年。存活率不到10%。中国国际刑事法院的特点是其高度恶性的促结缔组织再生障碍性疾病，以及大量的癌症-- 相关成纤维细胞(CAF)和细胞外基质(ECM)的作用仍然存在。有争议的原因是体内研究中的功能研究非常匮乏，而体外研究中的绝大多数国际刑事法院的研究则支持一项新的研究。最近的研究表明，CAF的促癌作用与胰腺癌的内源性发病有关，是一种高度危险的促结缔组织增生性疾病。肿瘤与国际刑事法院有许多相似之处，但已有研究表明，咖啡馆可以抑制癌症的生长。在这里，我们将寻求解决问题的方法。问题是，咖啡馆是应该促进国际刑事法院的发展，还是应该限制国际刑事法院的发展，而是使用大量的新技术和特定于细胞的技术工具来进行操纵。 CAF肿瘤细胞和肿瘤细胞在体内内源性地产生于ICC细胞中，我们假设CAF细胞和ECM细胞之间存在相互作用。提供一个利基市场，以促进国际商会的增长和生存，并提供对国际商会-CAF相声的详细描述。我们将在新的肿瘤微环境中确定新的治疗靶点。在目标1中，我们将无法确定其主要作用。 CAF正在使用一种新颖的工具来进一步确定CAF的遗传功能抑制或早期CAF消融以及晚期CAF消融将如何影响CAF的生长。增殖性细胞和抗凋亡性细胞信号转导通路，动物和小鼠的生存。在我们的目标2中，我们将继续调查这些通路。这将调解中国国际刑事法院对咖啡馆成员的招募、增殖和激活机制，并将重点放在可能导致肿瘤的假设上。细胞通过肿瘤来源的TGFb和PDGF1亚型和TGFb--介导正常的肝纤维化机制。激活整合素，从而促进咖啡馆的细胞积聚和激活。此外，还需要进行详细的机制研究。在基因敲除小鼠的体外和共培养中，我们还不能确定是否存在药物对CAF激活的抑制作用。 FDA批准的新药Nintdanib或其整合素阻断抗体可以抑制ICC的生长，并延长小鼠的生存时间。在目标3中，我们将不再确定CAF通过哪些途径来调节CICC的增长，而是专注于以下假设 CAF来源的ECM激活肿瘤细胞隔间的促肿瘤信号。为了检验这一假设，我们将研究具有CAF特异性COL1a1基因敲除或肿瘤选择性COL1a1基因敲除的小鼠的ICC发育胶原敏感受体盘状结构域受体1(DDR1)。此外，我们将确定ECM是否- 肿瘤细胞中机械敏感信号的介导僵硬和随后的激活促进ICC 发展。我们将测量肿瘤硬度、机械敏感信号通路和DDR1的激活在人类CCA样本中的表达，并将其与临床结果相关。刚性和DDR1在细胞周期调控中的作用 ICC生长和CAF-ICC串扰将在体外通过调节刚性和分别与缺乏COL1a1或DDR1的CAF和ICC细胞共培养。综上所述，该委员会提出了两项研究建议。中国将利用新的金融工具来回答国际金融领域一个长期存在的问题，并可能为中国国际刑事法院的目标定位提供更好的依据-- 咖啡馆的相声被认为是治疗这种毁灭性的恶性肿瘤的一种新颖的治疗策略。