Open AccessTGFβ selects for pro‐stemness over pro‐invasive phenotypes during cancer cell epithelial–mesenchymal transition
Author(s) -
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 CarlHenrik,
Moustakas Aristidis
Publication year - 2022
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.13215
Subject(s) - epithelial–mesenchymal transition , cancer research , mesenchymal stem cell , transforming growth factor , biology , transforming growth factor beta , microbiology and biotechnology , metastasis , cancer , genetics
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.