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Theranostics 2021; 11(17):8517-8534. doi:10.7150/thno.61006 This issue Cite

Research Paper

Generation of the tumor-suppressive secretome from tumor cells

Shengzhi Liu^1,2✉, Xun Sun^1,3, Kexin Li^1,3, Rongrong Zha^1,3, Yan Feng^1,3, Tomohiko Sano^1,4, Chuanpeng Dong⁵, Yunlong Liu⁵, Uma K. Aryal⁶, Akihiro Sudo⁴, Bai-Yan Li³, Hiroki Yokota^1,3,7,8✉

1. Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA
2. School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China
3. Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin 150081, China
4. Department of Orthopedic Surgery, Mie University, Mie 514, Japan
5. Center for Computational Biology and Bioinformatics, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
6. Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907, USA
7. Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN 46202, USA
8. Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA

✉ Corresponding authors: Shengzhi Liu, Ph.D. and Hiroki Yokota, Ph.D. Biomedical Engineering and Simon Cancer Center, Indiana University, 723 West Michigan Street, Indianapolis, IN 46202. s.l.: Phone: (317) 992-5626; E-mail: liu441edu; h.y.: Phone: (317) 278-5177; E-mail: hyokotaedu More

Abstract

Rationale: The progression of cancer cells depends on the soil and building an inhibitory soil might be a therapeutic option. We previously created tumor-suppressive secretomes by activating Wnt signaling in MSCs. Here, we examined whether the anti-tumor secretomes can be produced from tumor cells.

Methods: Wnt signaling was activated in tumor cells by overexpressing β-catenin or administering BML284, a Wnt activator. Their conditioned medium (CM) was applied to cancer cells or tissues, and the effects of CM were evaluated. Tumor growth in the mammary fat pad and tibia in C57BL/6 female mice was also evaluated through μCT imaging and histology. Whole-genome proteomics analysis was conducted to determine and characterize novel tumor-suppressing proteins, which were enriched in CM.

Results: The overexpression of β-catenin or the administration of BML284 generated tumor-suppressive secretomes from breast, prostate and pancreatic cancer cells. In the mouse model, β-catenin-overexpressing CM reduced tumor growth and tumor-driven bone destruction. This inhibition was also observed with BML284-treated CM. Besides p53 and Trail, proteomics analysis revealed that CM was enriched with enolase 1 (Eno1) and ubiquitin C (Ubc) that presented notable tumor-suppressing actions. Importantly, Eno1 immunoprecipitated CD44, a cell-surface adhesion receptor, and its silencing suppressed Eno1-driven tumor inhibition. A pan-cancer survival analysis revealed that the downregulation of MMP9, Runx2 and Snail by CM had a significant impact on survival outcomes (p < 0.00001). CM presented a selective inhibition of tumor cells compared to non-tumor cells, and it downregulated PD-L1, an immune escape modulator.

Conclusions: The tumor-suppressive secretome can be generated from tumor cells, in which β-catenin presented two opposing roles, as an intracellular tumor promoter in tumor cells and a generator of extracellular tumor suppressor in CM. Eno1 was enriched in CM and its interaction with CD44 was involved in Eno1's anti-tumor action. Besides presenting a potential option for treating primary cancers and metastases, the result indicates that aggressive tumors may inhibit the growth of less aggressive tumors via tumor-suppressive secretomes.

Keywords: breast cancer, β-catenin, Wnt signaling, enolase 1, ubiquitin C

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