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 9

Therapeutic inhibition of OPN enhances the efficacy of cisplatin in human and mouse ovarian cancer xenografts.

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Therapeutic inhibition of OPN enhances the efficacy of cisplatin in huma...
(A and B) Effect of preincubation with an anti-OPN Ab in the absence or presence of LP9-conditioned media on cisplatin sensitivity of OC8 subcutaneous tumors in immunodeficient mice (n = 7 mice per group). Tumor growth curves are shown in A. Xenograft weights at the end point are shown in B. Arrows show scheme of cisplatin treatment every 3 days for 3 cycles: magenta for LP9-conditioned media with control Ab groups, black for other groups. (C and D) Representative images (C) and quantification of cisplatin-DNA adduct immunofluorescence staining (D) in tumors of OC8 model. Quantification of positive cells (percentages of control media with control Ab group) is based on 5 random fields from 3 tumors in each group. Each dot represents 1 field. Nuclei were stained with DAPI (blue). Scale bars: 100 μm. (E and F) Representative images of tumor metastases (highlighted by white circles in E) in female C57BL/6J mice injected intraperitoneally with ID8 cells and then treated with a mutant OPN aptamer (mut apt) as control, cisplatin, OPN aptamer (OPN apt), or combination therapy (n = 9 mice per group). Tumor weight, tumor number, ascites volume, and omentum weights at the end point are shown in F. Each group is statistically compared with control group in F. Data are presented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001, 2-way ANOVA (A and B), 2-tailed Student’s t test (D) and 1-way ANOVA test (F).