Generation of the tumor-suppressive secretome from tumor cells

dc.contributor.authorLiu, Shengzhi
dc.contributor.authorSun, Xun
dc.contributor.authorLi, Kexin
dc.contributor.authorZha, Rongrong
dc.contributor.authorFeng, Yan
dc.contributor.authorSano, Tomohiko
dc.contributor.authorDong, Chuanpeng
dc.contributor.authorLiu, Yunlong
dc.contributor.authorAryal, Uma K.
dc.contributor.authorSudo, Akihiro
dc.contributor.authorLi, Bai-Yan
dc.contributor.authorYokota, Hiroki
dc.contributor.departmentBiomedical Engineering, School of Engineering and Technologyen_US
dc.date.accessioned2023-02-28T13:38:22Z
dc.date.available2023-02-28T13:38:22Z
dc.date.issued2021-07-25
dc.description.abstractRationale: 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.en_US
dc.eprint.versionFinal published versionen_US
dc.identifier.citationLiu S, Sun X, Li K, et al. Generation of the tumor-suppressive secretome from tumor cells. Theranostics. 2021;11(17):8517-8534. Published 2021 Jul 25. doi:10.7150/thno.61006en_US
dc.identifier.urihttps://hdl.handle.net/1805/31518
dc.language.isoen_USen_US
dc.publisherIvyspring Internationalen_US
dc.relation.isversionof10.7150/thno.61006en_US
dc.relation.journalTheranosticsen_US
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.sourcePMCen_US
dc.subjectBreast canceren_US
dc.subjectβ-cateninen_US
dc.subjectWnt signalingen_US
dc.subjectEnolase 1en_US
dc.subjectUbiquitin Cen_US
dc.titleGeneration of the tumor-suppressive secretome from tumor cellsen_US
dc.typeArticleen_US
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