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 8

Cancer-associated mesothelial cells promote ovarian cancer cell chemoresistance and ABC drug transporter activity through OPN, CD44, and PI3K/AKT signaling.

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Cancer-associated mesothelial cells promote ovarian cancer cell chemores...
(A and B) Effect of the anti-CD44 blocking Ab and/or integrin-blocking RGD peptide on LP9-conditioned media–mediated cisplatin resistance (A) or sphere-formation increase (B) of OC8 cells. Each group is statistically compared with LP9-conditioned media plus control Ab plus RGE group (n = 3 or 4). (C) Western blot showing PI3K/AKT signaling in OC8 cells cocultured with LP9 shControl or LP9 shOPN cells. (D) Western blot showing PI3K/AKT signaling in OC8 cells treated with exogenous OPN and/or anti-CD44 blocking Ab. (E) Effect of PI3K/AKT pathway inhibitor LY294002 on OPN-mediated cisplatin resistance of OC8 cells. Each group is statistically compared with exogenous OPN–alone group (n = 4). (F) Fold increase of relative mRNA expression of ABC transporters in OC8 with LP9 coculture versus OC8 monoculture, as normalized to GAPDH mRNA in real-time PCR analysis (n = 3). (G and H) Multidrug resistance assay detecting the activity of major types of ABC transporters (MDR1, MRP, and BCRP) in OC8 cells treated with LP9-conditioned media and/or anti-OPN Ab. Cyan histograms show dye retention of untreated cell, and red histograms show dye retention of respective inhibitor-treated cells in G. The same untreated cells in cyan are used in each row of histograms. Multidrug resistance activity factor (MAF) indicative of corresponding ABC drug transporter activity is shown in H and statistically compared with LP9-conditioned media plus control Ab group (n = 3). (I and J) Multidrug resistance assay detecting ABC transporter activity in OC8 cells treated with LP9-conditioned media and/or anti-CD44 blocking Ab (I) or the PI3K/AKT inhibitor LY294002 (J). MAF indicates corresponding ABC protein activity and is statistically compared with LP9-conditioned media or LP9-conditioned media plus control Ab group (n = 3). Data are presented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001, 2-way ANOVA (A, B, E, and H–J) and 2-tailed Student’s t test (F).