Cancer-associated mesothelial cells promote ovarian cancer chemoresistance through paracrine osteopontin signaling
Jin Qian, … , Oliver Dorigo, Erinn B. Rankin
Jin Qian, … , Oliver Dorigo, Erinn B. Rankin
Published August 16, 2021
Citation Information: J Clin Invest. 2021;131(16):e146186. https://doi.org/10.1172/JCI146186.
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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 2

Secreted factor or factors from cancer-associated mesothelial cells promote ovarian cancer chemoresistance.

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Secreted factor or factors from cancer-associated mesothelial cells prom...
(A–C) Effect of LP9 coculture on cisplatin resistance of OC8 cells in vivo. Tumor cells were indirectly cocultured with or without LP9 mesothelial cells in vitro and then were injected subcutaneously into immunodeficient mice, followed by treatment with or without cisplatin every 3 days for 3 cycles. Tumor growth curve is shown in A (n = 6–9 mice per group). Representative xenograft images are shown in B. Xenograft weights at the end point are shown in C. Arrows show scheme of cisplatin treatment: magenta arrows for mesothelial cell–conditioned groups, black arrows for unconditioned OC8 cell groups. (D and E) Effect of LP9 or LP3 coculture on the cisplatin sensitivity of OC8 cells. Cell viability is normalized to its untreated control and statistically compared with OC8 monoculture group (n = 3–5). (F) Percentages of annexin V+ apoptotic OC8 cells with or without LP9 preconditioning. Each group is statistically compared with OC8 monoculture group (n = 3). (G) Western blot analysis of cisplatin-induced apoptotic markers in OC8 after LP9 coculture. (H) Effect of conditioned media (CM) from HPMCs and cancer-associated mesothelial cells on OC8 cisplatin sensitivity. Cell viability is normalized to its untreated control and statistically compared with control media group (n = 3). Data are presented as mean ± SEM. **P < 0.05; ***P < 0.001, 2-way ANOVA (A, C–F, and H).