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: 10304429
• 负责人: Ernst Lengyel
• 金额: $ 32.39万
• 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/10304429
• 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; Image; Immune; Immune checkpoint inhibitor; Immunotherapy; In Vitro; Label; Laboratories; Lipids; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Mass Spectrum Analysis; 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; metabolomics; migration; mouse model; oxidation; research clinical testing; response; screening; small molecule inhibitor; therapy resistant; three dimensional cell culture; 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.

项目总结/摘要 转移性卵巢癌（OvCa）是妇科癌症死亡的主要原因。尽管进行了积极 化疗和手术后，大多数患者（80%）经历腹腔内进展或内脏复发， 腹腔里的脂肪组织15年多来，我的实验室一直致力于阐明 OvCa转移的生物学，重点是了解肿瘤微环境的失调 (TME)促进OvCa转移和化疗抗性。我们定义了多种基质的贡献， 细胞类型转移，揭示了甲基转移酶（NNMT）在正常细胞重编程中的关键作用。 成纤维细胞转化为癌症相关的成纤维细胞。此外，我们还回答了 为什么腹部转移性肿瘤倾向于转移到 网膜，发现脂肪因子吸引癌细胞到脂肪组织，脂肪细胞提供长链 脂肪酸通过β-氧化作用向癌细胞提供能量。然而，基本问题仍然存在， OvCa进展中的代谢过程。OvCa转移灶与原发灶在代谢上有何不同 肿瘤？化疗后哪些燃料/代谢物发生改变，它们如何促进化疗 抵抗？鉴于免疫疗法在几种上皮肿瘤中有效，其中一种更令人困惑， 及时的问题是为什么检查点抑制剂在OvCa中无效。我的假设是癌症与 脂肪细胞通过脂质驱动的免疫反应导致治疗抗性和免疫效应细胞耗竭 TME的代谢重编程。我们已经调整了方法来进行体内代谢通量分析， OvCa患者，通过输注标记的代谢物（非放射性13 C-葡萄糖，醋酸盐）， 使用成像质谱法优化肿瘤组织上的隔室分辨代谢组学的方法。 这些数据将使我们能够定义癌症，免疫和基质细胞前后的代谢变化 新辅助化疗这些研究所产生的假设将进行广泛的测试， 使用原代器官型3D培养物和小鼠模型的实验方法。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 活性测定，以及新设计的方法来测试自然杀伤细胞，T细胞， 巨噬细胞在体外和体内。对肿瘤器官中代谢变化的隔室特异性见解将 用于开展高通量筛查活动。这些应该会发现小分子抑制剂 这可以通过建立和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确定的代谢过程，我们可以大大增强抗肿瘤治疗， OvCa的反应，可能阻止这种致命疾病的无情进展特征。