Targeting Stromal Influences on Glutamine Addiction in Ovarian Cancer

靶向基质对卵巢癌谷氨酰胺成瘾的影响

• 批准号: 9754013
• 负责人: SAMUEL C MOK
• 金额: $ 45.77万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9754013
• 关键词: Adipocytes; Antioxidants; Blood Vessels; Cancer Cell Growth; Cancer Patient; Cancer cell line; Cancerous; Carbon; Cell Proliferation; Cells; Characteristics; Cisplatin; Coculture Techniques; Communication; Complex; Data; Dependence; Drug resistance; Endothelial Cells; Enzymes; Epithelial Cells; Extracellular Matrix Proteins; Failure; Fibroblasts; Generations; Glucose; Glutamate-Ammonia Ligase; Glutaminase; Glutamine; Glutathione; Growth; Immune; In Vitro; Knowledge; Label; Lead; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Mediating; Mesothelial Cell; Metabolic; Metabolism; Methods; Modality; Modeling; Neoplasm Metastasis; Normal tissue morphology; Nutrient; Operative Surgical Procedures; Ovarian Carcinoma; Paracrine Communication; Pathway interactions; Patients; Pericytes; Physiology; Public Health; Recurrence; Recurrent disease; Regulation; Resistance; Role; Site; Small Interfering RNA; Stromal Cells; Symbiosis; Testing; Time; Tissues; Tracer; Tumor Tissue; Up-Regulation; Work; addiction; base; cancer cell; cancer therapy; cell type; chemotherapy; deprivation; design; effective therapy; in vivo; intraovarian; loss of function; mouse model; new therapeutic target; novel; recruit; stable isotope; traditional therapy; transcriptomics; tumor; tumor metabolism; tumor microenvironment; tumor progression; two photon microscopy

PROJECT SUMMARY Despite advances in surgery and chemotherapy, ovarian cancer (OVCA) remains the most lethal gynecologic malignancy. The tumor microenvironment (TME) is a complex milieu of several types of cells, blood vessels and extracellular matrix proteins in which cancerous cells thrive. The cells that constitute most of the TME are fibroblasts, immune cells, endothelial cells and pericytes and are also collectively known as stroma. These cells become reactive and develop characteristics that support and even enhance tumor progression and metastasis due to proximity and constant interaction with cancer cells. Failure of traditional therapy is due to our limited understanding of how the TME can facilitate the rapid progression or recurrence of OVCA. Targeting reactive stromal cells is emerging as an attractive and viable therapy to regulate the channels of communication between stromal and cancer cells. To target non-autonomous mechanisms of cancer cell aberrations, the mechanistic underpinnings of reactive stroma vis a vis quiescent or normal stroma is required. Stromal cells such as cancer associated fibroblasts (CAFs), cancer associated mesothelial cells (CAMs), and cancer associated adipocytes (CAAs) in omental tissue have been shown to promote OVCA metastasis and growth. Although it has been recently shown that microenvironment can induce metabolic reprogramming in cancer cells, however, identification of stromal targets which make cancer cells vulnerable has remained challenging and elusive. We propose a previously unrecognized mechanism whereby metabolism of reactive stromal cells is reprogrammed through upregulated glutamine anabolic pathway. We first hypothesize that reactive stromal metabolism is altered from quiescent stroma, and is the driver for regulating cancer growth in its harsh microenvironment. Second, targeting this aberration could create metabolic vulnerability in cancer cells by disrupting the metabolic crosstalk between stromal and cancer cells. We will test these hypotheses in the proposed Aims. First, we will establish whether CAFs, CAAs, and CAMs promote OVCA cell proliferation by reprogramming glutamine (Gln) metabolism in cancer cells. We will validate upregulation of Gln anabolic pathway in reactive stromal cells compared to their normal counterparts through transcriptomic profiling. To elucidate metabolic reprogramming in reactive stromal cells we will use 13C-based metabolic flux analysis using stable isotope tracers to reveal metabolic vulnerabilities in stromal cells and unravel metabolic symbiosis between stromal and epithelial cells. Second, we will elucidate stroma-secreted Gln's role in maintaining OVCA cells' drug resistance. Our results will reveal an alternative modality in the treatment of recurrent OVCA. Third, we will determine the efficacy of targeting stromal Gln metabolism using orthotopic models of ovarian carcinoma and perform tracing of metabolic fates of different nutrients in tumors using in vivo tracer analysis in orthotopic models proposed for targeting stromal metabolism. In summary, our proposed study can lead to novel therapeutics targeting communication between cancer cells and their microenvironment.

项目总结 尽管在手术和化疗方面取得了进展，但卵巢癌(OVCA)仍然是最致命的妇科疾病 恶毒。肿瘤微环境(TME)是由多种类型的细胞、血管组成的复杂环境 以及癌细胞赖以生长的细胞外基质蛋白。构成TME的大部分细胞是 成纤维细胞、免疫细胞、内皮细胞和周细胞，也统称为间质。这些 细胞变得活跃，并形成支持甚至促进肿瘤进展的特征 由于接近癌细胞并不断与癌细胞相互作用而导致的转移。传统疗法的失败是由于 我们对TME如何促进OVCA的快速进展或复发的了解有限。 靶向反应性基质细胞正在成为一种有吸引力和可行的调节血管内皮细胞通道的方法 间质细胞和癌细胞之间的通讯。靶向癌细胞的非自主机制 像差，反应性间质相对于静止或正常间质的机械基础是必需的。 诸如癌相关成纤维细胞(CAF)、癌相关间皮细胞(CAM)等间质细胞， 而大网膜组织中的癌症相关脂肪细胞(CAA)已被证明促进OVCA的转移 和增长。尽管最近有研究表明，微环境可以诱导代谢重编程 然而，在癌细胞中，使癌细胞脆弱的间质靶点的鉴定仍然存在。 具有挑战性且难以捉摸。我们提出了一种以前不为人知的机制，即反应性代谢 基质细胞通过上调的谷氨酰胺合成代谢途径被重新编程。我们首先假设 反应性间质代谢从静止的间质改变，是调节肿瘤生长的驱动力。 它恶劣的微环境。其次，针对这种异常可能会在癌症中造成代谢脆弱性 通过扰乱基质细胞和癌细胞之间的代谢串扰。我们将在以下方面测试这些假设 建议的目标。首先，我们将确定CAF、CAA和CAM是否促进OVCA细胞的增殖 通过重新编程癌细胞中的谷氨酰胺(Gln)代谢。我们将验证Gln合成代谢的上调 通过转录转录图谱比较反应性基质细胞与正常基质细胞中的途径。至 阐明反应性基质细胞的代谢重编程我们将使用基于13C的代谢流量分析 利用稳定同位素示踪剂揭示基质细胞的代谢易损性和解开代谢共生 在间质细胞和上皮细胞之间。第二，我们将阐明基质分泌的谷氨酰胺在维持 OVCA细胞的耐药性。我们的结果将揭示一种治疗复发性OVCA的替代方法。 第三，我们将使用卵巢原位模型来确定靶向基质谷氨酰胺代谢的效果。 并使用体内示踪剂分析肿瘤中不同营养物质的代谢命运 提出了靶向基质代谢的原位模型。总而言之，我们提议的研究可以导致 针对癌细胞与其微环境之间的通讯的新型治疗药物。