TGFβ selects for pro‐stemness over pro‐invasive phenotypes during cancer cell epithelial–mesenchymal transition. Issue 12 (10th April 2022)

• Record Type: Journal Article
• Authors: Tsubakihara, Yutaro; Ohata, Yae; Okita, Yukari; Younis, Shady; Eriksson, Jens; Sellin, Mikael E.; Ren, Jiang; ten Dijke, Peter; Miyazono, Kohei; Hikita, Atsuhiko; Imamura, Takeshi; Kato, Mitsuyasu; Heldin, Carl‐Henrik; Moustakas, Aristidis
• Is Part Of: Molecular oncology. Volume 16:Issue 12(2022)
• Page Start: 2330
• Page End: 2354
• Publication Date: 2022-04-10
• Subjects: cancer stem cell -- E‐cadherin -- epithelial‐mesenchymal transition -- invasion -- metastasis -- transforming growth factor β; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1002/1878-0261.13215
• Languages: English
• ISSNs: 1574-7891

Abstract

Abstract : Transforming growth factor β (TGFβ) induces epithelial–mesenchymal transition (EMT), which correlates with stemness and invasiveness. Mesenchymal–epithelial transition (MET) is induced by TGFβ withdrawal and correlates with metastatic colonization. Whether TGFβ promotes stemness and invasiveness simultaneously via EMT remains unclear. We established a breast cancer cell model expressing red fluorescent protein (RFP) under the E‐cadherin promoter. In 2D cultures, TGFβ induced EMT, generating RFP low cells with a mesenchymal transcriptome, and regained RFP, with an epithelial transcriptome, after MET induced by TGFβ withdrawal. RFP low cells generated robust mammospheres, with epithelio‐mesenchymal cell surface features. Mammospheres that were forced to adhere generated migratory cells, devoid of RFP, a phenotype which was inhibited by a TGFβ receptor kinase inhibitor. Further stimulation of RFP low mammospheres with TGFβ suppressed the generation of motile cells, but enhanced mammosphere growth. Accordingly, mammary fat‐pad‐transplanted mammospheres, in the absence of exogenous TGFβ treatment, established lung metastases with evident MET (RFP high cells). In contrast, TGFβ‐treated mammospheres revealed high tumour‐initiating capacity, but limited metastatic potential. Thus, the biological context of partial EMT and MET allows TGFβ to differentiate between pro‐stemness and pro‐invasive phenotypes. Abstract : Whether TGFβ promotes stemness and invasiveness simultaneously via epithelial‐mesenchymal transition (EMT) still remains unclear. Using a breast cancer cell model expressing red fluorescent protein under the E‐cadherin promoter, we demonstrate that the biological context of partial mesenchymal–epithelial transition (pMET) enriches mammospheres with invasive and pro‐metastatic potential. Sustained partial EMT under TGFβ enriches mammospheres with a pro‐stemness phenotype with higher tumour‐initiating potential.