Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 256-260 |
| Number of pages | 5 |
| Journal | Nature |
| Volume | 525 |
| Issue number | 7568 |
| DOIs | |
| State | Published - Sep 10 2015 |
| Externally published | Yes |
Funding
Acknowledgements The pBl.1 and pBl.3 murine PyMT tumour cell lines, from which pBl.1G and pBl.3G were derived, were gifts from the Harold L. Moses laboratory. We thank G. Bell for helping analysing the ChIP-seq data. We thank R. Bronson for help assessing the histopathology of the murine tumours. We thank A. Lambert and S. Thiagalingam for providing the MCF10A-Ras and MCF10A-Ras-C cells. We thank W. Israelsen and M. Vander Heiden for providing the MMTV-cre;p531/2;BRCA1fl/fl murine mammary tumour samples. We thank the Keck Microscopy Facility at the Whitehead Institute for microscopy assistance and the Koch Institute Swanson Biotechnology Center (SBC) for technical support, especially the Histology and ES cell and Transgenics Cores. R.A.W. is an American Cancer Society and Ludwig Foundation professor. W.L.T. is supported by the National Research Foundation, Singapore (NRF-NRFF2015-04). This research was supported by the Breast Cancer Research Foundation, the Samuel Waxman Cancer Research Foundation, the Ludwig Center for Molecular Oncology at MIT, National Cancer Institute Program P01-CA080111, R01-CA078461, U01-CA184897 (to R.A.W.), K99-CA194160 (to X.Y.), the Wilshire Charitable Foundation/Andria and Paul Heafy Postdoctoral Fellowship (to X.Y.), the Mattina R. Proctor Foundation, and the Helen Hay Whitney Foundation (to X.Y.).
