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 1

Cancer-associated mesothelial cells promote ovarian cancer platinum resistance.

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Cancer-associated mesothelial cells promote ovarian cancer platinum resi...
(A–F) Effect of primary CAM1 (A–C) or LP9 (D–F) coinjection on cisplatin response of primary OC8 HGSOC cells in vivo. OC8 cells or OC8 cells plus LP9 or CAM1 mesothelial cells were injected subcutaneously into female immunodeficient mice and treated with or without cisplatin every 3 days for 3 cycles. Tumor growth curves are shown in A (n = 7–8 mice per group) and D (n = 5–7 mice per group). Representative xenograft images are shown in B and E. Xenograft weights at the end point are shown in C and F. Arrows show scheme of cisplatin treatment: magenta arrows for mesothelial cell–coinjected groups, black arrows for OC8 cell alone groups. (G–J) Representative images and quantification of cleaved caspase-3 (G and H) and γ-H2AX (I and J) immunofluorescence staining in OC8 and LP9 coinjected tumors. Scale bars: 100 μm. Quantification of positive cells (percentage of control) is based on 10 random fields from more than 3 tumors in each group. Each dot represents 1 field. Nuclei were stained with DAPI (blue). Data are presented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001, 2-way ANOVA (A, C, D, and F) and 2-tailed Student’s t test (H and J).