Cancer-associated mesothelial cells promote ovarian cancer chemoresistance through paracrine osteopontin signaling

Ovarian cancer is the leading cause of gynecological malignancy-related deaths, due to its widespread intraperitoneal metastases and acquired chemoresistance. Mesothelial cells are an important cellular component of the ovarian cancer microenvironment that promote metastasis. However, their role in...

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Published inThe Journal of clinical investigation Vol. 131; no. 16; pp. 1 - 16
Main Authors Qian, Jin, Lesavage, Bauer L, Hubka, Kelsea M, Ma, Chenkai, Natarajan, Suchitra, Eggold, Joshua T, Xiao, Yiren, Fuh, Katherine C, Krishnan, Venkatesh, Enejder, Annika, Heilshorn, Sarah C, Dorigo, Oliver, Rankin, Erinn B
Format Journal Article
LanguageEnglish
Published Ann Arbor American Society for Clinical Investigation 01.08.2021
Subjects
1-Phosphatidylinositol 3-kinase
AKT protein
Apoptosis
Ascites
Biomedical research
Cancer therapies
CD44 antigen
Cell activation
Chemoresistance
Chemotherapy
Cisplatin
Gynecology
Malignancy
Medical prognosis
Metastases
Metastasis
Microenvironments
Osteopontin
Ovarian cancer
Paracrine signalling
Therapeutic targets
Tumors
Xenografts
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Summary:Ovarian cancer is the leading cause of gynecological malignancy-related deaths, due to its widespread intraperitoneal metastases and acquired chemoresistance. Mesothelial cells are an important cellular component of the ovarian cancer microenvironment that promote metastasis. However, their role in chemoresistance is unclear. Here, we investigated whether cancer-associated mesothelial cells promote ovarian cancer chemoresistance and stemness in vitro and in vivo. We found that osteopontin is a key secreted factor that drives mesothelial-mediated ovarian cancer chemoresistance and stemness. Osteopontin is a secreted glycoprotein that is clinically associated with poor prognosis and chemoresistance in ovarian cancer. Mechanistically, ovarian cancer cells induced osteopontin expression and secretion by mesothelial cells through TGF-ß signaling. Osteopontin facilitated ovarian cancer cell chemoresistance via the activation of the CD44 receptor, PI3K/AKT signaling, and ABC drug efflux transporter activity. Importantly, therapeutic inhibition of osteopontin markedly improved the efficacy of cisplatin in both human and mouse ovarian tumor xenografts. Collectively, our results highlight mesothelial cells as a key driver of ovarian cancer chemoresistance and suggest that therapeutic targeting of osteopontin may be an effective strategy for enhancing platinum sensitivity in ovarian cancer.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI146186.