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Linking EMT programmes to normal and neoplastic epithelial stem cells

Abstract

Epithelial stem cells serve critical physiological functions in the generation, maintenance and repair of diverse tissues through their ability to self-renew and spawn more specialized, differentiated cell types. In an analogous fashion, cancer stem cells have been proposed to fuel the growth, progression and recurrence of many carcinomas. Activation of an epithelial–mesenchymal transition (EMT), a latent cell-biological programme involved in development and wound healing, has been linked to the formation of both normal and neoplastic stem cells, but the mechanistic basis underlying this connection remains unclear. In this Perspective, we outline the instances where aspects of an EMT have been implicated in normal and neoplastic epithelial stem cells and consider the involvement of this programme during tissue regeneration and repair. We also discuss emerging concepts and evidence related to the heterogeneous and plastic cell states generated by EMT programmes and how these bear on our understanding of cancer stem cell biology and cancer metastasis. A more comprehensive accounting of the still-elusive links between EMT programmes and the stem cell state will surely advance our understanding of both normal stem cell biology and cancer pathogenesis.

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Fig. 1: Overview of EMT programmes.
Fig. 2: EMT programmes in normal epithelial stem cells.
Fig. 3: EMT heterogeneity during metastatic colonization.
Fig. 4: Dynamics of EMT progression.
Fig. 5: Mechanistic connections between EMT programmes and the epithelial stem cell state.

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Acknowledgements

The authors thank the past and present members of the Weinberg laboratory and the MIT Stem Cell Initiative for many discussions that have helped to shape the ideas presented in this Perspective. They also thank C. Rausch for initial preparation of the figures. A.W.L. was supported by an American Cancer Society — New England Division — Ellison Foundation Postdoctoral Fellowship (PF-15-131-01-CSM) and a postdoctoral fellowship from the Ludwig Center for Molecular Oncology at MIT. Research in the Weinberg laboratory is supported by the MIT Stem Cell Initiative through Fondation MIT, the Breast Cancer Research Foundation, the Ludwig Center for Molecular Oncology at MIT and grants R01-CA078461 and R35-CA220487 (to R.A.W.) from the National Institutes of Health, National Cancer Institute Program. R.A.W. is an American Cancer Society Research Professor and a Daniel K. Ludwig Cancer Research Professor.

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Correspondence to Robert A. Weinberg.

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A.W.L. declares no competing interests. R.A.W. is an adviser to and holds shares in Verastem Inc.

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Lambert, A.W., Weinberg, R.A. Linking EMT programmes to normal and neoplastic epithelial stem cells. Nat Rev Cancer (2021). https://doi.org/10.1038/s41568-021-00332-6

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