Cancer-associated mesothelial cells promote ovarian cancer chemoresistance through paracrine osteopontin signaling
Jin Qian, Bauer L. LeSavage, Kelsea M. Hubka, Chenkai Ma, Suchitra Natarajan, Joshua T. Eggold, Yiren Xiao, Katherine C. Fuh, Venkatesh Krishnan, Annika Enejder, Sarah C. Heilshorn, Oliver Dorigo, Erinn B. Rankin
Jin Qian, Bauer L. LeSavage, Kelsea M. Hubka, Chenkai Ma, Suchitra Natarajan, Joshua T. Eggold, Yiren Xiao, Katherine C. Fuh, Venkatesh Krishnan, Annika Enejder, Sarah C. Heilshorn, Oliver Dorigo, Erinn B. Rankin
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Research Article Oncology

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

Abstract

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-β 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.

Authors

Jin Qian, Bauer L. LeSavage, Kelsea M. Hubka, Chenkai Ma, Suchitra Natarajan, Joshua T. Eggold, Yiren Xiao, Katherine C. Fuh, Venkatesh Krishnan, Annika Enejder, Sarah C. Heilshorn, Oliver Dorigo, Erinn B. Rankin

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Figure 5

Cancer-associated mesothelial cells secrete OPN.

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Cancer-associated mesothelial cells secrete OPN. (A) Cytokine array in c...
(A) Cytokine array in conditioned media of HPMC1 and CAM1. Circles highlight cytokine of the highest increase in CAM1- compared with HPMC1-conditioned media in each individual color. (B) Quantification of OPN concentration in conditioned media from HPMCs and CAMs by ELISA (n = 2 or 3). (C) Volcano plot of RNA-Seq showing differential gene expression in CAMs versus HPMCs (GSE84829). (D) Real-time PCR analysis of relative mRNA expression of OPN in HPMCs and CAMs, as normalized to GAPDH mRNA (n = 3). (E) Immunofluorescence of OPN (red) and mesothelial cell marker calretinin (green) in total ascites cells from HGSOC patients. Arrowheads denote costained mesothelial cells. Nuclei were stained with DAPI (blue). Scale bars: 100 μm. (F) Percentages of total OPN-positive cells in paired calretinin+ and calretinin– ascites cells of ovarian cancer patients (n = 14). (G) Correlation of ascites OPN concentration and calretinin+ cell percentages in total ascites cells of ovarian cancer patients (n = 14; Pearson’s correlation). (H) Correlation of OPN and calretinin expression in total ascites cells of ovarian cancer patients (n = 13; Pearson’s correlation). Data are presented as mean ± SEM. ***P < 0.001, 2-tailed Student’s t test (F).