Stromal and vascular inputs into pancreatic cancer tumor neighborhoods

胰腺癌肿瘤邻域的基质和血管输入

基本信息

批准号：
10733718
负责人：
M. CELESTE SIMON
金额：
$ 66.43万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-15 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10733718
关键词：
Address Angiogenesis Inhibitors B-Lymphocytes Biological Blood Vessels Cell division Cells Chemoresistance Clinical Clinical Trials Data Data Set Desmoplastic Development Ecosystem Endothelial Cells Exhibits Fibroblasts Genetically Engineered Mouse Geography Goals Heterogeneity Human Hypervascular Hypoxia Implant Invaded Lipids Lymphatic Malignant Neoplasms Malignant neoplasm of pancreas Metabolic Microscopy Modeling Molecular Neighborhoods Nutrient Oxygen Pancreatic Ductal Adenocarcinoma Pathway interactions Proteins Source Techniques Therapeutic Unsaturated Fatty Acids Vascular Endothelial Cell Vascular Endothelium cancer cell clinically relevant cohort coping human data human tissue improved innovation insight lipid metabolism mouse model neoplastic cell pancreatic cancer cells pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model patient subsets precision medicine regional difference response supply chain tissue resource treatment strategy tumor tumor heterogeneity tumor microenvironment

项目摘要

PROJECT SUMMARY Cancer cells are the organizers of their surroundings and create a tumor microenvironment (TME) favoring cell division even when oxygen and nutrients are limiting. An extreme example is pancreatic ductal adenocarcinoma (PDAC) which establishes a metabolically hostile ecosystem characterized by a hypo-vascular, severely hypoxic, and nutrient deprived stroma. Clinical trials targeting components of the PDAC stroma have not improved overall survival in unselected cohorts. Thus, while opportunities for targeting the PDAC TME exist, the development of anti-stromal therapies will require a better understanding of inter- and intra-tumoral heterogeneity. Our labs have studied two features of the PDAC stroma: the vasculature and CAFs. By analyzing multiple human datasets, and mouse models, we found that a significant portion of human PDACs (~10%) are hyper-vascular. In murine models, hyper-vascularity is associated with increased sensitivity to angiogenesis inhibitors. In addition, our preliminary studies have shown that in the more typical hypo-vascular tumors, hypoxia renders PDAC tumor cells incapable of synthesizing unsaturated fatty acids (uFAs), and therefore critically dependent upon lipids supplied by neighboring CAFs for their survival. Based on these data, we hypothesize that cancer- associated micro-vasculature and lipid secreting fibroblasts represent under-exploited, clinically relevant targets within the PDAC stroma. Here, we propose an innovative approach to delineate the cellular mechanisms by which tumor cells build and maintain critical metabolic “supply chains” and how regional differences within tumors influence nutrient utilization and vascular intravasation. Our proposal addresses both basic and translational questions and utilizes human tissue resources, implantable and genetically engineered mouse models, platforms to assess stromal geography and metabolic features, and cancer-on-chip techniques for ex vivo modeling. Our ultimate goal is to understand and manipulate the major sources from which PDAC cells derive essential nutrients (especially vital uFAs) – focusing on micro-vessels and fibroblasts. Aim 1. Determine the causes and consequences of vascular heterogeneity in PDAC Aim 2. Delineate molecular mechanisms and therapeutic opportunities underlying stromal support of lipid metabolism in PDAC

项目概要癌细胞是周围环境的组织者，并创造有利于细胞的肿瘤微环境（TME）即使氧气和营养物质有限，细胞也会分裂。一个极端的例子是胰腺导管腺癌。（PDAC），它建立了一个代谢不利的生态系统，其特征是血管不足、严重缺氧、针对 PDAC 基质成分的临床试验总体上没有改善。因此，虽然存在针对 PDAC TME 的机会，但开发抗基质疗法需要更好地了解肿瘤间和肿瘤内的异质性。我们的实验室通过分析多个人体，研究了 PDAC 基质的两个特征：脉管系统和 CAF。通过数据集和小鼠模型，我们发现很大一部分人类 PDAC（约 10%）是富血管的。在小鼠模型中，血管丰富与对血管生成抑制剂的敏感性增加有关。此外，我们的初步研究表明，在更典型的缺血管肿瘤中，缺氧会导致 PDAC 肿瘤细胞无法合成不饱和脂肪酸 (uFA)，因此严重依赖根据邻近 CAF 为其生存提供的脂质，我们捕获了这种癌症—— 相关的微脉管系统和脂质分泌成纤维细胞代表了未充分利用的临床相关目标在 PDAC 基质内。在这里，我们提出了一种创新方法来描述肿瘤细胞构建和形成的细胞机制。维持关键的代谢“供应链”以及肿瘤内的区域差异如何影响营养我们的建议解决了基本问题和转化问题并利用。人体组织资源、可植入和基因工程小鼠模型、评估基质的平台我们的最终目标是利用地理和代谢特征以及用于离体建模的芯片上癌症技术。了解和操纵 PDAC 细胞获取必需营养素（尤其是重要营养素）的主要来源 uFA）——专注于微血管和成纤维细胞。目标 1. 确定 PDAC 血管异质性的原因和后果目标 2. 描述基质支持的分子机制和治疗机会 PDAC中的脂质代谢