Norepinephrine induces anoikis resistance in high-grade serous ovarian cancer precursor cells
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.
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JCI InsightInstitutions
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Funding
Project 3: Investigating new treatment approaches based on DNA repair vulnerability in ARID1A mutated type I ovarian cancerImaging mass spectrometry methodologies for studying the metabolites of cancer metastasisHigh-Resolution Dynamic Imaging of Ovarian Cancer Metastasis Post ChemotherapyProject 3: Investigating new treatment approaches based on DNA repair vulnerability in ARID1A mutated type I ovarian cancerImaging mass spectrometry methodologies for studying the metabolites of cancer metastasisHigh-Resolution Dynamic Imaging of Ovarian Cancer Metastasis Post ChemotherapyImaging mass spectrometry methodologies for studying the metabolites of cancer metastasisU.S. Department of Defense Grant W81XWH-22-1-0852Dr. Miriam and Sheldon G. Adelson Medical Research Foundation Grant NAHonorable Tina Brozman Foundation Grant NAMarsha Rivkin Center for Ovarian Cancer Research Grant NAClaneil Foundation Grant NAMike and Patti Hennessy Foundation Grant NAHelene Ross Bogutz Fund for Ovarian Cancer Early Detection Grant NAThe Marjorie S. Stanek and Lowell H. Dubrow Ovarian Cancer Research Center Endowed Fund Grant NAThe Basser Center for BRCA Grant NACarl H. Goldsmith Ovarian Cancer Translational Research Fund Grant NARichard and Sharyn Berman Ovarian Cancer Early Detection Fund Grant NAMonica K. Young Foundation Grant NA