Norepinephrine induces anoikis resistance in high-grade serous ovarian cancer precursor cells

Abstract

High-grade serous carcinoma (HGSC) is the most lethal gynecological malignancy in the United States. Late diagnosis and the emergence of chemoresistance have prompted studies into how the tumor microenvironment, and more recently tumor innervation, may be leveraged for HGSC prevention and interception. In addition to stess-induced sources, concentrations of the sympathetic neurotransmitter norepinephrine (NE) in the ovary increase during ovulation and after menopause. Importantly, NE exacerbates advanced HGSC progression. However, little is known about the role of NE in early disease pathogenesis. Here, we investigated the role of NE in instigating anchorage independence and micrometastasis of preneoplastic lesions from the fallopian tube epithelium (FTE) to the ovary, an essential step in HGSC onset. We found that in the presence of NE, FTE cell lines were able to survive in ultra-low-attachment (ULA) culture in a β-adrenergic receptor–dependent (β-AR–dependent) manner. Importantly, spheroid formation and cell viability conferred by treatment with physiological sources of NE were abrogated using the β-AR blocker propranolol. We have also identified that NE-mediated anoikis resistance may be attributable to downregulation of colony-stimulating factor 2. These findings provide mechanistic insight and identify targets that may be regulated by ovary-derived NE in early HGSC.

Fallopian Tube-Derived High-Grade Serous Cancers Influence Ovarian Production of Norepinephrine and Generate Specific Metabolomic Signatures

“…These data suggest that specific mutations or species characteristics can both uniquely and generally alter the metabolome and, by extension, the tumor microenvironment. This observation can also be inferred from other recent literature demonstrating that distinct human fallopian tube cell lines respond heterogeneously to treatment with NE . From a wider lens, it is clear that each cell line has a unique way of interacting with the ovary, and this in turn creates unique metabolomes.…”

“…The literature demonstrates that in human FTE, NE treatment has been shown to increase compact spheroid formation and cell viability while cotreatment with propranolol abrogates these effects . To further investigate the role of NE in this context, we next conducted in vitro assays modeling tumor biology to further study the effects of NE signaling, including proliferation and spheroid formation.…”