PI3K-activated MSC proteomes inhibit mammary tumors via Hsp90ab1 and Myh9

Xun Sun; Kexin Li; Uma K Aryal; Bai-Yan Li; Hiroki Yokota

doi:10.1016/j.omto.2022.08.003

PI3K-activated MSC proteomes inhibit mammary tumors via Hsp90ab1 and Myh9

Mol Ther Oncolytics. 2022 Aug 5:26:360-371. doi: 10.1016/j.omto.2022.08.003. eCollection 2022 Sep 15.

Authors

Xun Sun^{1

2}, Kexin Li^{1

2}, Uma K Aryal³, Bai-Yan Li¹, Hiroki Yokota^{1

2

4

5}

Affiliations

¹ Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin 150081, China.
² Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA.
³ Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907, USA.
⁴ Indiana Center for Musculoskeletal Health, Indianapolis, IN 46202, USA.
⁵ Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

Abstract

Despite the advance in medications in the past decade, aggressive breast cancer such as triple-negative breast cancer is difficult to treat. Here, we examined a counter-intuitive approach to converting human bone marrow-derived mesenchymal stem cells (MSCs) into induced tumor-suppressing cells by administering YS49, a PI3K/Akt activator. Notably, PI3K-activated MSCs generated tumor-suppressive proteomes, while PI3K-inactivated MSCs tumor-promotive proteomes. In a mouse model, the daily administration of YS49-treated MSC-derived CM decreased the progression of primary mammary tumors as well as the colonization of tumor cells in the lung. In the ex vivo assay, the size of freshly isolated human breast cancer tissues, including estrogen receptor positive and negative as well as human epidermal growth factor receptor 2 (HER2) positive and negative, was decreased by YS49-treated MSC-derived CM. Hsp90ab1 was enriched in CM as an atypical tumor-suppressing protein and immunoprecipitated a non-muscle myosin, Myh9. Extracellular Hsp90ab1 and Myh9 exerted the anti-tumor action and inhibited the maturation of bone-resorbing osteoclasts. Collectively, this study demonstrated that the activation of PI3K generated tumor-suppressive proteomes in MSCs and supported the possibility of using patient-derived MSCs for the treatment of breast cancer and bone metastasis.

Keywords: Hsp90ab1; MSC; Myh9; PI3K/Akt; bone metastasis; breast cancer.