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Adipose stromal cell targeting suppresses prostate cancer epithelial-mesenchymal transition and chemoresistance

Abstract

Fat tissue, overgrowing in obesity, promotes the progression of various carcinomas. Clinical and animal model studies indicate that adipose stromal cells (ASC), the progenitors of adipocytes, are recruited by tumors and promote tumor growth as tumor stromal cells. Here, we investigated the role of ASC in cancer chemoresistance and invasiveness, the attributes of tumor aggressiveness. By using human cell co-culture models, we demonstrate that ASC induce epithelial-mesenchymal transition (EMT) in prostate cancer cells. Our results for the first time demonstrate that ASC interaction renders cancer cells more migratory and resistant to docetaxel, cabazitaxel, and cisplatin chemotherapy. To confirm these findings in vivo, we compared cancer aggressiveness in lean and obese mice grafted with prostate tumors. We show that obesity promotes EMT in cancer cells and tumor invasion into the surrounding fat tissue. A hunter-killer peptide D-CAN, previously developed for targeted ASC ablation, suppressed the obesity-associated EMT and cancer progression. Importantly, cisplatin combined with D-CAN was more effective than cisplatin alone in suppressing growth of mouse prostate cancer allografts and xenografts even in non-obese mice. Our data demonstrate that ASC promote tumor aggressiveness and identify them as a target of combination cancer therapy.

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Acknowledgements

We thank A. Daquinag, Z. Gao, and W. Cao for discussions and technical support.

Funding

This study was supported by NIH grant R01 CA196259 (to JD and MK), R21 CA216745 (to MK) and the Harry E. Bovay, Jr. Foundation.

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Correspondence to Mikhail G. Kolonin.

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The authors declare that they have no conflict of interest.

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Su, F., Ahn, S., Saha, A. et al. Adipose stromal cell targeting suppresses prostate cancer epithelial-mesenchymal transition and chemoresistance. Oncogene 38, 1979–1988 (2019). https://doi.org/10.1038/s41388-018-0558-8

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