Abstract B091: Mechanisms underlying the omental support of ovarian cancer peritoneal metastasis
Authors: Rachel Mintz, Alexandre Gallerand, Jichang Han, Sarah Ning, Wei Zou, Mary Wohltmann, Bernd Zinselmeyer, Gwendalyn Randolph
Journal: Cancer Research (2024)

Abstract More than 80% of ovarian cancer (OC) cases have metastasized to the peritoneal cavity at diagnosis. The five-year survival rate for these patients is 25%. Within the peritoneal cavity, the most common and early site of metastasis is the omentum, a well-vascularized, specialized adipose tissue that arises off the greater curvature of the stomach. Because OC homes to the omentum, it is removed as a standard of care for patients with peritoneal metastases. In mouse models, the omentum is also an early metastatic site, and omentectomy reduces tumor expansion. The mechanism by which the omentum promotes OC growth is unknown, perhaps due to the complex omental microenvironment. The omentum contains many features that could impact OC seeding. It is covered by a mesothelial lining that extends in a sheet anchoring the omentum to surrounding tissues and is highly perfused by blood vessels. It contains lymphoid aggregates or milky spots that may contribute to pro- and anti-tumor immunity. This study explores the association of OC metastases with specific omentum features. We intraperitoneally injected luciferase-expressing ID8 OC cells to mimic high-grade serous OC metastasis. Using high-resolution, spatial ex vivo bioluminescence imaging (BLI), we found that tumor nodules preferentially formed in adipocyte-rich regions of the omentum and the mesentery, another peritoneal tissue favorable for OC seeding. To determine whether adipocytes, the most abundant omental cell type, are the primary support of OC, we crossed Adiponectin Cre+ and DTA mice to generate mice lacking white and brown adipocytes from birth. To overcome the metabolic syndrome the fatless mice develop, they receive subcutaneous fat transplants dorsally, referred to as distal adipocyte rescue of lipodystrophy (DARL) mice. Littermate controls receive sham surgeries. The blood triglyceride, glucose, and insulin levels are normalized post-transplant. Thus, the peritoneal cavity lacks mature adipocytes, but the mice have typical metabolic profiles, allowing us to study the role of omental adipocytes in peritoneal metastasis. Once the mice recovered from surgery, they were intraperitoneally injected with luciferase-expressing ID8s. While it was hypothesized that OC metastatic seeding within the adipocyte-free omentum and associated peritoneum would be impaired without local mature adipocytes, BLI revealed that the tumor burden was not decreased in DARL mice. Notably, specific regions of OC seeding, where mature adipocytes would have localized if present, such as the omentum and mesentery, retained tumor nodules in DARL mice. This conserved OC localization suggests that other cells in this specific microenvironment might be responsible for metastatic spread. To identify these cells, studies are ongoing to profile these regions in the DARL and control mice via flow cytometry and single-cell RNA sequencing. By unraveling the support for OC cells in the omentum, therapeutic strategies can be identified to repolarize the metastatic milieu and halt further spread to improve patient outcomes. Citation Format: Rachel Mintz, Alexandre Gallerand, Jichang Han, Sarah Ning, Wei Zou, Mary Wohltmann, Bernd Zinselmeyer, Gwendalyn Randolph. Mechanisms underlying the omental support of ovarian cancer peritoneal metastasis [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B091.