Omental Preadipocytes Stimulate Matrix Remodeling and IGF Signaling to Support Ovarian Cancer Metastasis

Jennifer A. Waters, Mikella Robinson, Omar Lujano-Olazaba, Cassidy Lucht, Samuel F. Gilbert, Carrie D. House
In: Cancer Research · 2024 · vol. 84(13) , pp. 2073–2089 · doi:10.1158/0008-5472.can-23-2613 · PMID:38635891 · W4394909208
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Abstract

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. An 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. Coculturing with preadipocytes led to the 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. IGF1 induced ECM genes and increased alternative NF-κB signaling by activating RelB. Inhibiting the IGF1 receptor initially increased tumor omental adhesion but decreased the 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. Significance: Omental preadipocyte-mediated IGF1 signaling promotes ovarian cancer tumorigenesis and metastasis via extracellular matrix remodeling, revealing a role for preadipocytes in regulating ovarian cancer progression and highlighting potential therapeutic targets for metastatic disease.

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