Abstract 3453: TNF augments ovarian cancer metastasis in an omentum-independent manner

Abstract The mechanistic role of the inflammatory cytokine tumor necrosis factor (TNF) in ovarian cancer pathogenesis has been widely debated. The Randolph lab has developed a new mouse model, TNFD69Au, in which CRISPR/Cas9 was used to target the 3’ AU rich-response element of TNF mRNA transcripts in immunocompetent C57BL/6J mice, resulting in increased stability of TNF RNA and thus elevated inflammation. When TNFD69Au mice and their wild-type (WT) littermate controls were intraperitoneally injected with the aggressive ID8p53-/-Brca2-/- murine ovarian cancer cell line that recapitulates high-grade serous ovarian cancer, the TNFD69Au mice had significantly increased tumor burden compared to their littermates as early as one-week post-injection. This discrepancy continued consistently until the endpoint when ascites accumulated. The greater omentum, a visceral fat pad along the stomach, is a well-established early and predominant metastatic niche in ovarian cancer. Yet, the TNFD69Au mice demonstrate broad tumor dissemination across peritoneal organs with minimized omental preference. When TNFD69Au mice were omentectomized, their tumor burden was equivalent to that of TNFD69Au mice that received sham surgery, while WT mice expectedly exhibited decreased tumor burden when omentectomized. Regardless of omentectomy, the tumor burden in these TNFD69Au mice was higher than in WT mice, highlighting how increased TNF production in the peritoneal cavity leads to increased tumor burden independent of the omentum. To determine if the source of TNF driving the elevated tumor burden was hemopoietic-derived, bone marrow from TNFD69Au mice or WT littermates was transplanted into WT or TNFD69Au mice recipients. TNFD69Au mice that received bone marrow from WT or TNFD69Au mice had increased tumor burden compared to WT mice that received WT bone marrow. These results suggest that the elevated TNF responsible for increased tumor burden can be stromal-derived, which is surprising given the canonical role of hematopoietic cells in TNF-signaling. Altogether, our data suggest that TNF increases peritoneal ovarian cancer spread and minimizes omental dominance, potentially through stromal signaling. Citation Format: Rachel L. Mintz, 1 Emma E. Erlich, 2 Heather S. Ruiz, 1 Quazim Alayo, 1 Mary Wohltmann, 1 Gwendalyn J. Randolph1. TNF augments ovarian cancer metastasis in an omentum-independent manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3453.