Identifying and Targeting Metabolic Dependencies in the Pancreatic Tumor Microenvironment

识别和靶向胰腺肿瘤微环境中的代谢依赖性

基本信息

批准号：
10186710
负责人：
Mara H. Sherman
金额：
$ 35.23万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
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：
2018-07-12 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10186710
关键词：
Ablation Biological Assay Biomass Cancer Etiology Cell Differentiation process Cell Surface Receptors Cell Survival Cell physiology Cells Cellular Metabolic Process Cessation of life Clinic Coculture Techniques Consumption Data Dependence Desmoplastic Enzymes Epithelial Epithelial Cell Proliferation Extracellular Matrix Extracellular Space Fatty Acids Fibroblasts Fostering Genes Genetic Genetic Transcription Goals Growth Human In Vitro Lipids Lysophosphatidylcholines Lysophospholipids Malignant Neoplasms Malignant neoplasm of pancreas Metabolic Metabolic Pathway Mitogens Mus Nutrient Oxygen Pancreas Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Pharmacology Phenotype Prognosis Property Reaction Regulation Role Route Serum Signal Transduction Stromal Cells System Testing Therapeutic Therapeutic Intervention Tissues Tumor-infiltrating immune cells United States Work cancer cell cell growth cell transformation cell type density improved in vivo in vivo Model lipid metabolism lipidome lipidomics lysophosphatidic acid mouse model novel novel therapeutic intervention overexpression pancreatic cancer cells pancreatic cancer patients pancreatic ductal adenocarcinoma cell pancreatic neoplasm pancreatic stellate cell pancreatic tumorigenesis paracrine programs response stable isotope stellate cell targeted treatment therapeutic target tumor microenvironment tumorigenesis wound healing

项目摘要

PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) cells maintain proliferative capacity despite a hypovascular, nutrient- poor microenvironment; this challenging microenvironment is established by cancer-associated fibroblasts (CAFs). PDAC CAFs are predominantly derived from pancreatic stellate cells (PSCs), lipid-storing cells in healthy pancreas which can transdifferentiate to an activated CAF phenotype and generate a dense, desmoplastic stroma. CAF-derived components generate an oxygen- and nutrient-poor microenvironment to which PDAC cells must adapt. These adaptation mechanisms remain poorly understood, and may represent vulnerabilities for therapeutic intervention. Our recent results suggest that paracrine lipid flux from PSC-derived CAFs represents a novel mechanism by which the stroma provides energy and pro-proliferative signals to cancer cells to support PDAC growth. Specifically, we find that PDAC CAFs secrete abundant lysophosphatidylcholine (LPC), the preferred fatty acid scavenging substrate for Ras-transformed cells such as PDAC cells; the PDAC CAF secretome also contains high levels of lysophosphatidic acid (LPA), an established mitogen with multiple downstream effectors with roles in tumorigenesis. Our preliminary transcriptional and lipidomic data suggest that PSCs undergo a dramatic lipid metabolic shift in the context of pancreatic tumorigenesis, including remodeling of the intracellular lipidome and secretion of abundant lipids in the activated CAF state. These results raise the possibility that PDAC CAFs secrete specific lipid species that act in a paracrine manner to “feed” the epithelial compartment and stimulate proliferation. We hypothesize that fibroblastic cells function via secreted lipids to promote epithelial cell proliferation and survival in the context of an inhospitable wound-healing response. This hypothesis will be tested with the following specific aims. Aim 1: Understand the effect of stroma-derived lipids on cancer cell lipid metabolism. A stable isotope tracing approach will be used to determine the extent of paracrine metabolic flux from stromal cells to cancer cells among secreted lipids, and alterations to PDAC cell metabolism in response to stroma-derived lipids will be assessed using established metabolic assays. Aim 2: Determine the role of stroma-derived lipids in PDAC cell growth control. Established in vitro culture and co-culture systems will be used to analyze regulation of mitogenic LPA effectors pathways and growth capacity in response to stroma-derived lipids. Aim 3: Define the significance of the LPC-Autotaxin-LPA axis in microenvironmental regulation of pancreatic cancer growth in vivo. LPA is generated from LPC by secreted enzyme Autotaxin; we find that LPC is secreted at high levels by PDAC CAFs, and that ATX is overexpressed in mouse and human PDAC. The LPC-Autotaxin-LPA axis will be interrogated both genetically and pharmacologically in a PDAC mouse model in vivo to determine its role in PDAC progression. These studies will improve our understanding of PDAC cell survival and growth mechanisms in the context of a nutrient-poor tumor microenvironment, potentially identifying a novel route for therapeutic intervention.

项目摘要/摘要胰腺导管腺癌（PDAC）细胞尽管不血管，营养不良，但仍保持增殖能力贫穷的微环境；这种挑战微环境是由癌症相关的成纤维细胞建立的（CAFS）。 PDAC CAF主要源自胰腺星状细胞（PSC），健康的脂质存储细胞胰腺可以转化为活化的CAF表型并产生致密的脱塑料基质。 CAF衍生的成分产生了氧气和营养贫困的微环境，PDAC细胞至必须适应。这些适应机制的理解仍然很差，可能代表了治疗干预。我们最近的结果表明，来自PSC衍生CAF的旁分泌脂质通量代表基质的一种新型机制，可为癌细胞提供能量和促销信号以支持 PDAC增长。具体而言，我们发现PDAC CAFS秘密富含溶血磷脂酰胆碱（LPC），首选的脂肪酸清除RAS转换细胞（如PDAC细胞）的底物； PDAC CAF 分泌组还含有高水平的溶物磷脂酸（LPA），这是一种已建立的有丝分裂原，多个下游效应在肿瘤发生中作用。我们的初步转录和脂肪组数据表明在胰腺肿瘤发生的背景下，PSC经历了戏剧性的脂质代谢转移，包括重塑细胞内脂肪组和活化CAF状态中丰富脂质的分泌。这些结果提高了 PDAC CAFS以旁分泌作用以“喂”上皮的秘密特异性脂质物种车厢并刺激增殖。我们假设成纤维细胞通过分泌的脂质发挥作用在不可避免的伤口治疗反应的背景下，促进上皮细胞增殖和存活。这假设将以以下特定目的进行检验。目标1：了解基质衍生的效果癌细胞脂质代谢的脂质。稳定的同位素跟踪方法将用于确定程度分泌脂质中从基质细胞到癌细胞的旁分泌代谢通量，并改变了PDAC细胞对基质衍生脂质的响应的代谢将使用已建立的代谢测定法进行评估。目标2：确定基质衍生的脂质在PDAC细胞生长控制中的作用。建立的体外培养和共培养系统将用于分析有丝分裂LPA效应途径和生长能力的调节响应基质衍生的脂质。 AIM 3：定义LPC-Autotaxin-LPA轴的重要性体内胰腺癌生长的微环境调节。 LPA由LPC由分泌产生酶自动昔候；我们发现PDAC CAF在高水平分泌LPC，并且ATX过表达在小鼠和人类PDAC中。 LPC-Autotaxin-LPA轴将在遗传和在体内PDAC小鼠模型中，在药理学上确定其在PDAC进程中的作用。这些研究会在营养贫困肿瘤的背景下，提高我们对PDAC细胞存活和生长机制的理解微环境，有可能识别一种新的治疗干预途径。