Abstract 2189: The role of generational obesity on the ovarian metastatic niche
Authors: Hilliard Tyvette , Petrasko Phillip , Liu Yueying , Yang Jing , Asem Marwa , Johnson Jeff , Marfowaa Gifty , Kowalski Brooke , Schnautz Elinor , McCabe Morgan , Stack M. Sharon 
Published: June 2022

Obesity is a worldwide epidemic associated with many cancer types due to persistent inflammation, hyperglycemia and hyperinsulinemia providing an abundance of nutrients and growth factors to cancer cells resulting in an ideal microenvironment. Maternal obesity often results in an increased risk of offspring developing obesity. Chronic inflammation and immunosuppression found in obese patients have been linked to ovarian cancer (OvCa). OvCa is the most lethal gynecological malignancy among women and approximately 12% of OvCa patients are obese. Poor survival rates are attributable to women presenting with advanced disease with disseminated intraperitoneal (i.p) metastasis at diagnosis. Metastatic tumor cells shed from the primary tumor and preferentially home to the mesothelium of the omentum and other peritoneal organs producing secondary lesions. Developmental programming suggests that perinatal nutritional influences can alter gene expression in offspring. A pre-clinical murine model of diet-induced obesity that included maternal cohorts of C57BL/6 mice (dam) with intact host immunity fed either a control diet (CD; 10% fat) or a high-fat diet (HFD; 40% fat) and the resulting offspring fed either diet was utilized to explore diet induced genetic and physical modifications. Body composition analysis revealed differences in weight and lean mass was dependent on offspring diet alone and fat mass was dam diet dependent among CD fed offspring. Second harmonic generation microscopy demonstrated a larger area of collagen mesh-work between fenestrations in the omentum of HFD fed mice as well as an increase in anisotropy. Additionally, a tumor study was performed using either CD or HFD fed offspring to quantify site-specific metastatic success to the adipose-rich tissues of the peritoneal cavity. Mice were injected i.p. with fluorescently tagged syngeneic ID8 murine OvCa cells and disease progression was tracked for 8 weeks. Abdominal organs were dissected, imaged, and organ-specific tumor burden quantified. Overall, offspring fed a HFD displayed an increase in organ-specific tumor burden relative to offspring fed a CD, regardless of dam diet. Furthermore, HFD offspring from HFD dams displayed higher omental tumor burden than HFD offspring from CD dams. In addition, HFD fed mice accumulated more ascites fluid than CD fed mice, however variances were independent of dam diet. Comparison of ascites cytokine expression revealed CXCL13, a dominant chemokine in adipocytes, was significantly increased in mice only exposed to a HFD suggesting an additive effect of both maternal and offspring obesity. Interestingly, increased CXCL13 expression has been reported in OvCa cell lines and in clinical samples. Together, the results suggest maternal obesity or subsequent exposure to a HFD can influence ovarian cancer metastasis.

Citation Format: Tyvette Hilliard, Phillip Petrasko, Yueying Liu, Jing Yang, Marwa Asem, Jeff Johnson, Gifty Marfowaa, Brooke Kowalski, Elinor Schnautz, Morgan McCabe, M. Sharon Stack. The role of generational obesity on the ovarian metastatic niche [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2189.