Metabolic reprogramming of the tumor microenvironment and therapy resistance

肿瘤微环境的代谢重编程和治疗抵抗

• 批准号: 10470867
• 负责人: Ernst Lengyel
• 金额: $ 96.43万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-17 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10470867
• 关键词: Abdomen; Abdominal Cavity; Acetates; Adhesions; Adipocytes; Adipose tissue; Biochemical; Biological Assay; Biology; Cancer Patient; Cause of Death; Cellular Assay; Characteristics; Chemoresistance; Chemotherapy-Oncologic Procedure; Data; Disease; Effector Cell; Epithelial; Fibroblasts; Glucose; Immune; Immune checkpoint inhibitor; Immunotherapy; In Vitro; Label; Laboratories; Lipids; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Metabolic; Metabolism; Methods; Methyltransferase; Natural Killer Cells; Neoadjuvant Therapy; Neoplasm Metastasis; Omentum; Operative Surgical Procedures; Organ; Patients; Primary Neoplasm; Process; Production; Recurrence; Resistance; Role; Stromal Cells; Structure; T-Lymphocyte; Testing; Time; Tumor Tissue; Visceral; adipokines; cancer cell; cell type; chemotherapy; confocal imaging; defined contribution; exhaustion; experience; immune function; in vivo; insight; long chain fatty acid; macrophage; mass spectrometric imaging; metabolomics; migration; mouse model; oxidation; research clinical testing; screening; small molecule inhibitor; therapy resistant; three dimensional cell culture; treatment response; tumor; tumor microenvironment; tumor progression

PROJECT SUMMARY/ABSTRACT Metastatic ovarian cancer (OvCa) is the leading cause of death from gynecologic cancer. Despite aggressive chemotherapy and surgery, most patients (80%) experience intraabdominal progression or recurrence to visceral adipose tissue in the abdominal cavity. For more than 15 years, my laboratory has concentrated on elucidating the biology of OvCa metastasis, focusing on understanding how deregulation of the tumor microenvironment (TME) promotes OvCa metastasis and chemotherapy resistance. We defined the contribution of multiple stromal cell types to metastasis, revealing a critical role for a methyltransferase (NNMT) in the reprogramming of normal fibroblasts into cancer-associated fibroblasts through metabolic remodeling. Additionally, we answered the decades-old question of why abdominally metastasizing tumors have a propensity to metastasize to the omentum, finding that adipokines attract cancer cells to adipose tissue, and that adipocytes provide long-chain fatty acids to cancer cells for energy production through β-oxidation. However, fundamental questions remain about metabolic processes in OvCa progression. How are OvCa metastases metabolically different from primary tumors? Which fuels/metabolites are altered after chemotherapy, and how do they contribute to chemotherapy resistance? Given that immunotherapies are effective in several epithelial tumors, one of the more puzzling and timely questions is why checkpoint inhibitors are ineffective in OvCa. My hypothesis is that cancer associated adipocytes contribute to therapy resistance and immune effector cell exhaustion through the lipid-driven metabolic reprogramming of the TME. We have adapted methods to perform in vivo metabolic flux analysis in OvCa patients, by infusing labeled metabolites (non-radioactive 13C-glucose, acetate) and are working on methods to optimize compartment resolved metabolomics on tumor tissue using imaging mass spectrometry. These data will allow us to define metabolic changes in cancer, immune, and stromal cells before and after neoadjuvant chemotherapy. The hypotheses generated by these studies will be tested with wide-ranging experimental approaches using primary organotypic 3D cultures and mouse models. Our experimental approach will span functional cellular assays (to study adhesion, migration, and invasion), confocal imaging, biochemical activity assays, and newly devised methods to test the functionality of natural killer cells, T-cells, and macrophages in vitro and in vivo. Compartment-specific insights into metabolic changes in the tumor organ will be employed to develop high-throughout screening campaigns. These should discover small molecule inhibitors that can be optimized through an established and structured process towards clinical testing. We believe that, by targeting metabolic processes identified in the tumor organ, we can greatly enhance anti-tumor therapy response in OvCa, potentially halting the inexorable progression characteristic of this deadly disease.

项目摘要/摘要 转移性卵巢癌（OVCA）是妇科癌症死亡的主要原因。尽管有进取心 化学疗法和手术，大多数患者（80％）经历腹部进展或内脏复发 腹腔中的脂肪组织。 15多年来，我的实验室集中于阐明 OVCA转移的生物学，重点是了解肿瘤微环境的放松管制如何 （TME）促进OVCA转移和化学疗法抗性。我们定义了多个基质的贡献 转移的细胞类型，揭示了甲基转移酶（NNMT）在正常重编程中的关键作用 通过代谢重塑，成纤维细胞成癌症相关的成纤维细胞。此外，我们回答了 几十年来的问题是为什么腹部转移肿瘤有望转移到该肿瘤的问题 omentum，发现脂肪因子吸引癌细胞进入脂肪组织，并且脂肪细胞提供长链 脂肪酸通过β氧化来产生能量的癌细胞。但是，基本问题仍然存在 关于OVCA进展的代谢过程。 OVCA转移与主要不同 肿瘤？哪些燃料/代谢物在化学疗法后会改变，以及它们如何促进化学疗法 反抗？鉴于免疫疗法在几种上皮肿瘤中有效，这是一个更难题和 及时的问题是为什么检查点抑制剂在OVCA中无效。我的假设是癌症 脂肪细胞有助于通过脂质驱动的治疗耐药性和免疫效应细胞耗尽 TME的代谢重编程。我们采用了对体内代谢通量分析进行的调整方法 OVCA患者，通过注入标记的代谢产物（非放射性13c-葡萄糖，乙酸），正在研究 使用成像质谱法在肿瘤组织上优化隔室的代谢组学的方法。 这些数据将使我们能够在癌症，免疫细胞和基质细胞中定义代谢变化 新辅助化疗。这些研究产生的假设将通过广泛测试 实验方法使用主要有机3D培养物和小鼠模型。我们的实验方法 将涵盖功能性细胞测定（研究粘附，迁移和侵袭），共聚焦成像，生化 活动评估以及新设计的方法来测试天然杀伤细胞，T细胞和 体外和体内巨噬细胞。对肿瘤器官代谢变化的隔室特异性见解将 被用来开发高直接筛选活动。这些应该发现小分子抑制剂 可以通过建立且结构化的临床测试过程来优化。我们相信 通过靶向肿瘤器官中鉴定的代谢过程，我们可以大大增强抗肿瘤治疗 OVCA的反应，有可能停止这种致命疾病的不可驱动的进展特征。