Distinct EMT programs control normal mammary stem cells and tumour-initiating cells

By X. Ye, W. Tam, T. Shibue, Yasemin Kaygusuz, Ferenc Reinhardt, E. Eaton, R. Weinberg. Nature, 2015

662 citations recorded by the source corpus.

Tumour-initiating cells (TICs) are responsible for metastatic dissemination and clinical relapse in a variety of cancers. Analogies between TICs and normal tissue stem cells have led to the proposal that activation of the normal stem-cell program within a tissue serves as the major mechanism for generating TICs. Supporting this notion, we and others previously established that the Slug epithelial-to-mesenchymal transition-inducing transcription factor (EMT-TF), a member of the Snail family, serves as a master regulator of the gland-reconstituting activity of normal mammary stem cells, and that forced expression of Slug in collaboration with Sox9 in breast cancer cells can efficiently induce entrance into the TIC state. However, these earlier studies focused on xenograft models with cultured cell lines and involved ectopic expression of EMT-TFs, often at non-physiological levels. Using genetically engineered knock-in reporter mouse lines, here we show that normal gland-reconstituting mammary stem cells residing in the basal layer of the mammary epithelium and breast TICs originating in the luminal layer exploit the paralogous EMT-TFs Slug and Snail, respectively, which induce distinct EMT programs. Broadly, our findings suggest that the seemingly similar stem-cell programs operating in TICs and normal stem cells of the corresponding normal tissue are likely to differ significantly in their details.

Subfields: Genetics, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/5d15a9ba1da82b7e1afc2928a4c317654f780709

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Citations in the corpus

Epithelial–mesenchymal transition in tumor metastasis (2016, background): “When SNAIL1-YFP-positive cells (and not SNAIL2-YFP-positive cells) isolated from primary tumors were introduced into mice by tail vein injection or subcutaneous implantation (Ye et al., 2015), they also formed significantly more metastases.”
Dynamic EMT: a multi‐tool for tumor progression (2021, positive): “Similarly, in squamous cell carcinoma (SCC) TWIST is regulating BMI1 to cooperatively repress CDKN2A (p16 INK4A ) and promote tumor initiation capacities (Yang et al , 2010).”
EMT, MET, plasticity and tumor metastasis (2020, background): “Thus, it is not surprising that a PyMT model with Snail-driven YFP resulted in YFP+ cells lacking Cdh1 and Zeb1 expression [21].”
Systems Biology of Cancer Metastasis (2019, background): “…evidence suggesting that single or clusters of cells could disseminate from the primary tumor mass(Aceto et al., 2014; Massague and Obenauf, 2016; Ye et al., 2015; Yu et al., 2013), and that these programs are both cell intrinsic(Alexander et al., 2008), and triggered in response to the…”
EMERGING BIOLOGICAL PRINCIPLES OF METASTASIS (2017, positive): “In fact, detailed histopathological analyses of invasive cohorts often suggest that the EMT does indeed participate in collective migration (Ye et al., 2015).”
The molecular mechanisms and therapeutic strategies of EMT in tumor progression and metastasis (2022, background): “In a relevant mouse breast cancer model, by tracking the endogenous SNAIL activation, it was found that only primary tumors had SNAIL1 activation and endogenous EMT production [182, 190].”
Epithelial-mesenchymal plasticity in cancer progression and metastasis (2019, background): “Using genetically engineered reporter mouse model to follow the endogenous expression of SNAI1 during cancer progression, it was shown that SNAI1 activation and EMT indeed occur in primary tumor cells that ultimately disseminate and that SNAI1 is essential for the metastasis of mouse mammary carcino”