Ovarian cancer is the most lethal gynecological cancer with limited therapeutic options and a complex tumor microenvironment (TME). The TME provides signals that support ovarian cancer progression, and many of these signals are secreted by the fat-precursor cells of the nearby omentum, or omental preadipocytes. The omentum is a dynamic endocrine organ and during metastasis it is the first site of invasion with the largest tumor burden. While adipocytes have been shown to encourage cancer cell homing and provide metabolic support, the role of preadipocytes in tumorigenesis is unclear and warrants further investigation I have shown that preadipocytes are required for tumorigenesis of ovarian cancer cells when in low dilutions in a subcutaneous mouse model. Moreover, preadipocytes secrete factors that enhance tumor cell viability by increasing proliferation in nutrient-poor environments and enable increased colony formation at low dilution. RNA sequencing data indicate that ovarian cancer cells upregulate an extracellular matrix (ECM) gene program in the presence of secreted factors from preadipocytes, with increased expression of different collagen isoforms as well as members of the insulin-like growth factor binding protein (IGFBP) family. Within this dataset I discovered that IGFBP5 was the most upregulated gene in ovarian cancer cells co-cultured with preadipocytes, followed closely by COL1A2, COL6A2, FN1 and MMP2.
The IGFBPs, including IGFBP5, regulate IGF-1, which is elevated in the cancer cells in co-culture and induces expression of COL1A2 and COL6A2, indicating a potential role for IGF-1 in regulating ECM remodeling in the TME. Interestingly, expression of IGFBP5 was found to increase between early and late stages of tumorigenesis, in contrast to the other ECM genes studied. In cells with IGFBP5 knockdown, the tumor growth rate decreased, indicating that increased IGFBP5 contributes to tumor growth in response to omental preadipocytes. This study proposes a new link between preadipocytes and ovarian cancer tumorigenesis via ECM remodeling and expression of IGFBP5, with implications for tumor metastasis.