Abstract B078: Insulin-like growth factor signaling contributes to omental preadipocyte-mediated tumorigenesis in ovarian cancer by regulating expression of extracellular matrix genes
Authors: Waters Jennifer A. , Robinson Mikella , Lujano-Olazaba Omar , Gilbert Samuel F. , House Carrie D. 
Published: March 2024

Abstract
Ovarian cancer is the most lethal gynecological malignancy in the United States, with a known predilection for metastasizing to the omentum, a sheet of fatty tissue that encloses the abdomen. While it has been shown that ovarian cancer cells invade towards mature adipocytes in vitro, the contribution of stromal cells that reside in the omentum is not well understood. Our preliminary data indicate that preadipocytes, the precursor cells that give rise to omental adipocytes, support tumorigenesis in ovarian cancer cells in a subcutaneous injection limiting-dilution model. This phenotype is specific to a low dilution of cancer cells, and a transplantation assay further showed that cancer cells require the presence of preadipocytes for sustained tumor formation capacity in vivo. Preadipocyte-secreted factors additionally altered tumorgenicity of ovarian cancer cells as tested via colony formation and cell viability in vitro. To identify signaling pathways induced by preadipocytes we co-cultured cancer cells with either primary human omental preadipocytes or differentiated mature adipocytes derived from the same female donor and performed RNA sequencing and gene set enrichment analysis. We identified differentially expressed genes in cancer cells that were upregulated in preadipocyte co-culture, including COL1A1, COL1A2, MMP2 and COL6A2, all genes involved in extracellular matrix organization. Among the most significantly upregulated genes was insulin-like growth factor binding protein 5 (IGFBP5), which has functions in insulin-like growth factor signaling (IGF) and ECM interactions. We hypothesized that the IGF signaling axis was activated in preadipocyte-stimulated tumors, and that inhibiting this pathway would negatively impact tumorigenesis in response to omental preadipocytes. Indeed, when the low dilution of the subcutaneous tumor model with preadipocytes was treated with NVP-AEW541, an inhibitor of the IGF1 receptor (IGF1R), tumor growth was significantly blunted relative to the vehicle control. Furthermore, the concentration of the IGF1 ligand is elevated in cancer cell/preadipocyte co-cultures, and treatment with exogenous IGF1 results in elevated expression of several of the ECM genes identified in the RNA sequencing, including COL1A2 and COL6A2. Silencing COL1A2 prevents a significant increase in cell viability in response to preadipocyte-conditioned media, indicating that upregulation of collagen 1 is important for cancer cell persistence under low-serum and low dilution conditions. Our findings highlight the role of preadipocytes in the ovarian tumor microenvironment and implicate IGF signaling in matrix remodeling to support early tumorigenesis. Future studies will determine if there is a link between the upregulation of IGFBP5 and modulation of preadipocyte-regulated IGF signaling. Understanding these processes will enable the design of more effective therapies for treating advanced ovarian cancer.
Citation Format: Jennifer A. Waters, Mikella Robinson, Omar Lujano-Olazaba, Samuel F. Gilbert, Carrie D. House. Insulin-like growth factor signaling contributes to omental preadipocyte-mediated tumorigenesis in ovarian cancer by regulating expression of extracellular matrix genes [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 B078.