TGFβ selects for pro-stemness over pro-invasive phenotypes during cancer cell epithelial-mesenchymal transition

Mol Oncol. 2022 Jun;16(12):2330-2354. doi: 10.1002/1878-0261.13215. Epub 2022 Apr 10.


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 RFPlow cells with a mesenchymal transcriptome, and regained RFP, with an epithelial transcriptome, after MET induced by TGFβ withdrawal. RFPlow 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 RFPlow 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 (RFPhigh 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.

Keywords: E-cadherin; cancer stem cell; epithelial-mesenchymal transition; invasion; metastasis; transforming growth factor β.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Epithelial-Mesenchymal Transition*
  • Humans
  • Lung Neoplasms*
  • Phenotype
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta / metabolism


  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta

Associated data

  • RefSeq/E-MTAB-97509