Abstract 6436: Metabolic masquerade: glutamine's role in ovarian cancer dynamics

Abstract Most patients with high-grade serous ovarian cancer (HGSC) are diagnosed at advanced stages. Despite the high response rate to platinum/taxane-based chemotherapy, most of these patients develop recurrent chemoresistant disease. Recent studies showed that cancer associated fibroblasts (CAF) in the tumor microenvironment (TME) play an important role in modulating the malignant phenotypes of HGSC. CAFs are primarily responsible for producing factors such as cytokines to modify the TME niche and promote the malignant phenotypes of cancer cells. We have recently identified a previously unrecognized mechanism in which metabolic reprogramming through an upregulated glutamine anabolic pathway in reactive CAF within HGSC tissue. This dysfunctional metabolic pathway confers atypical metabolic flexibility and adaptive mechanisms in CAF, allowing them to harness carbon and nitrogen from noncanonical sources to synthesize glutamine in nutrient-deprived conditions existing in the TME. We showed that C57BL/6 mice injected with syngeneic fallopian epithelial cell-derived cancer cells and fed with normal diet had significantly higher tumor burden than those fed with the glutamine-free (GF) diet. Moreover, tumor-bearing mice treated with glutaminase inhibitor for 3 weeks demonstrated significantly lower tumor burden than those treated with the control vehicle. These findings suggest that glutamine depletion can not only suppress ovarian tumor growth but also prevent the development of advanced progressive diseases. To further determine whether the tumor immune microenvironment modulates the effect of glutamine deprivation on decreasing tumor burden in mice, imaging mass cytometry (IMC) and Mass Spectrometry Imaging (MSI) were performed on serial tissue sections of tissue microarrays generated from the abovementioned murine samples. The results showed that mice fed with a GF diet or treated with the glutaminase inhibitor not only had a significantly lower tumor burden but also had dramatic changes in the cellular and molecular composition within the TME. In particular, mice fed with a GF diet had markedly greater B-cell-related immune response, reduced stemness and EMT of ovarian cancer cells, and lower activated CAF density in the tumor tissue compared to mice fed with the control diet. Further studies to delineate the molecular mechanisms by which spatial cellular and metabolic profiles modulate HGSC progression revealed that the neighborhood of EPCAM+ PANCK+ tumor cells was significantly more populated with several cell types, including neutrophils, in the GF diet than the control mice. This neighborhood was also significantly enriched in certain metabolic signatures including Kynurenic acid (KYNA) and Indole-3-Carbinol (13C). Further studies to delineate the role of glutamine in metabolic reprogramming of the ovarian tumor immune microenvironment are warranted. Citation Format: Sammy Ferri-Borgogno, Olamide Animasahun, Basant Gamal, Erin Seeley, Kathryn Lu, Javier A. Gomez, Akshay Basi, Jared K. Burks, Deepak Nagrath, Samuel C. Mok. Metabolic masquerade: glutamine's role in ovarian cancer dynamics [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 6436.