Stromal and vascular inputs into pancreatic cancer tumor neighborhoods

项目摘要 癌细胞是其周围环境的组织者，并创造有利于细胞增殖的肿瘤微环境（TME）。 即使氧气和营养物质有限，也能进行分裂。一个极端的例子是胰腺导管腺癌 （PDAC），其建立了一个代谢敌对的生态系统，其特征在于低血管，严重缺氧， 和缺乏营养的基质。针对PDAC基质成分的临床试验总体上没有改善 存活率因此，虽然存在针对PDAC TME的机会， 抗基质治疗需要更好地理解肿瘤间和肿瘤内的异质性。 我们的实验室已经研究了PDAC基质的两个特征：血管和CAF。通过分析多个人类 通过比较数据集和小鼠模型，我们发现很大一部分人PDAC（~10%）是多血管的。 在鼠模型中，血管过多与对血管生成抑制剂的敏感性增加相关。在 此外，我们的初步研究表明，在更典型的低血管肿瘤中，缺氧使 PDAC肿瘤细胞不能合成不饱和脂肪酸（uFAs），因此严重依赖 依靠邻近的CAF提供的脂质生存。基于这些数据，我们假设癌症- 相关的微血管系统和脂质分泌成纤维细胞代表未充分开发的临床相关靶点 在PDAC基质中。 在这里，我们提出了一种创新的方法来描绘肿瘤细胞的细胞机制， 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 利用和血管内渗。我们的建议解决了基本问题和翻译问题，并利用 人类组织资源，可植入和基因工程小鼠模型，评估基质的平台 地理和代谢特征，以及用于离体建模的癌症芯片技术。我们的最终目标是 了解和操纵PDAC细胞获得必需营养素的主要来源（特别是重要的 uFAs）-集中于微血管和成纤维细胞。 目标1。确定PDAC中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

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