Omental preadipocytes stimulate matrix remodeling and IGF signaling to support ovarian cancer metastasis

Ovarian cancer can metastasize to the omentum, which is associated with a complex tumor microenvironment. Omental stromal cells facilitate ovarian cancer colonization by secreting cytokines and growth factors. Improved understanding of the tumor supportive functions of specific cell populations in the omentum could identify strategies to prevent and treat ovarian cancer metastasis. Here, we showed that omental preadipocytes enhance the tumor initiation capacity of ovarian cancer cells. Secreted factors from preadipocytes supported cancer cell viability during nutrient and isolation stress and enabled prolonged proliferation. Co-culturing with pre-adipocytes led to upregulation of genes involved in extracellular matrix (ECM) organization, cellular response to stress, and regulation of insulin-like growth factor (IGF) signaling in ovarian cancer cells. IGF-1 induced ECM genes and increased alternative NF-κB signaling by activating RelB. Inhibiting the IGF-1 receptor (IGF1R) initially increased tumor omental adhesion but decreased growth of established preadipocyte-induced subcutaneous tumors as well as established intraperitoneal tumors. Together, this study shows that omental preadipocytes support ovarian cancer progression, which has implications for targeting metastasis. ACI-23 ovarian cancer cells were co-cultured with omental preadipocytes and differentiated lipid-storing adipocytes for 6 days. Co-cultures were set up to replicate the low cancer cell to high stromal cell density of early metastasis at a 1:40 ratio with 500 cancer cells and 20,000 preadipocytes/adipocytes. Co-cultures were performed using transwell chambers to allow the for exchange of secreted factors, and all RNA sequencing data was relativized to mono-culture controls.