Mechanisms Underlying the Omental Support of Ovarian Cancer Peritoneal Metastasis

卵巢癌腹膜转移的大网膜支持机制

• 批准号: 10678068
• 负责人: Rachel Mintz
• 金额: $ 5.27万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678068
• 关键词: Adipocytes; Adipose tissue; Advisory Committees; Affect; Architecture; B-Lymphocytes; Back; Binding; Blood Vessels; Cancer Model; Cancer Patient; Cardiovascular system; Cells; Data; Diagnosis; Distal; Enzymes; Fatty Acids; Fatty acid glycerol esters; Flow Cytometry; Fluorescence; Fostering; Greater curvature of stomach; Greater sac of peritoneum; Growth; Hematogenous; Image; Immune; Impairment; Label; Lipodystrophy; Location; Lymphoid; Macrophage; Maintenance; Malignant neoplasm of ovary; Mentorship; Metabolic; Metabolic syndrome; Microscopy; Monitor; Mus; Neoplasm Metastasis; Observational Study; Omentum; Oncologist; Pathway interactions; Patient Care; Patients; Peritoneal; Peritoneum; Phenotype; Physicians; Population; Primary Neoplasm; Proliferating; Role; Route; Scientist; Site; Spottings; Stains; Stromal Cells; Supporting Cell; T-Lymphocyte; Testing; Therapeutic; Time; Training; Transplantation; Travel; Tumor Burden; Tumor Expansion; Tumor Promotion; Vascularization; bioluminescence imaging; cancer cell; cancer seeding; career; design; effective therapy; fluorescence imaging; implantation; improved; improved outcome; insight; intraperitoneal; mouse model; novel therapeutic intervention; ovarian neoplasm; peritoneal cancer; single-cell RNA sequencing; standard of care; subcutaneous; treatment strategy; tumor; tumor growth; tumor progression

PROJECT SUMMARY More than 80% of ovarian cancer (OC) cases have already metastasized to the peritoneal cavity at diagnosis, and the five-year survival for these patients is 25%. Within the peritoneal cavity, the most common site of metastasis is the omentum, a well-vascularized, specialized adipose tissue that arises off the greater curvature of the stomach. Because the omentum promotes tumor growth, it is removed as a standard of care for patients with peritoneal metastases. In mouse OC models, the omentum is an early metastatic site, and removing the omentum before tumor implantation reduces the pace of tumor expansion. Once OC cells shed from the primary tumor and form spheroids, some bind to the adjacent omentum, which is considered transcoelomic metastasis. Other data show that OC cells can exit the peritoneal cavity and travel back to the omentum via the circulatory system, underscoring a hematogenous peritoneal metastatic pathway. Overall, the mechanism by which the omentum promotes tumor growth is still unknown and is important to identify so that we can develop more specific therapeutic strategies. Studies suggest that omental macrophages, blood vessels, or lymphoid aggregates called milky spots, are key features that support tumor growth. In addition to these omental features, the adipocytes themselves, the cells that define the omentum as a fat pad, are likely important for tumor expansion. Adipocytes can directly provide fatty acids to metabolically support tumor proliferation or may indirectly foster tumor growth by supporting milky spot formation, as my preliminary data suggest. To move beyond these valuable observational studies, I herein propose using a mouse model wherein the mouse lacks white and brown adipocytes, rendering the peritoneal cavity adipocyte-free, to explore the role of the omentum in OC metastasis without mature adipocytes. Due to a total lack of fat, the mice become lipodystrophic. To overcome this systemic metabolic syndrome, the lipodystrophic mice receive subcutaneous fat transplants, referred to as distal adipocyte rescue of lipodystrophy (DARL) mice. Littermate controls also receive the fat transplant, known as DARC mice for distal adipose-receiving control mice. I hypothesize that the metastatic seeding and dissemination of murine OC cells within the adipocyte-free omentum and associated peritoneum will be impaired in the absence of local, mature adipocytes. While testing this hypothesis, I will assess how the loss of omental adipocytes impacts the overall omental architecture in DARL mice. I will analyze the impact of an adipocyte-free versus adipocyte-rich omentum on tumor growth. Lastly, I will explore the role of hematogenous and transcoelomic spread to the adipocyte-rich or adipocyte-free omentum and consider whether omentum cells support tumors as spheroids that disseminate within the peritoneal cavity. I will pursue these aims under the mentorship of an advisory committee that includes physician-scientists. This training will help improve my understanding of metastasis so that I can ultimately identify new treatment strategies in my career as an oncologist-scientist.

项目总结