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Shaping epithelial tissues by stem cell mechanics in development and cancer

Nature Reviews Molecular Cell Biology (2025)Cite this article

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Abstract

Adult stem cells balance self-renewal and differentiation to build, maintain and repair tissues. The role of signalling pathways and transcriptional networks in controlling stem cell function has been extensively studied, but there is increasing appreciation that mechanical forces also have a crucial regulatory role. Mechanical forces, signalling pathways and transcriptional networks must be coordinated across diverse length and timescales to maintain tissue homeostasis and function. Such coordination between stem cells and neighbouring cells dictates when cells divide, migrate and differentiate. Recent advances in measuring and manipulating the mechanical forces that act upon and are produced by stem cells are providing new insights into development and disease. In this Review, we discuss the mechanical forces involved when epithelial stem cells construct their microenvironment and what happens in cancer when stem cell niche mechanics are disrupted or dysregulated. As the skin has evolved to withstand the harsh mechanical pressures from the outside environment, we often use the stem cells of mammalian skin epithelium as a paradigm for adult stem cells shaping their surrounding tissues.

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Fig. 1: Epithelial stem cells mechanically sculpt their niches in development and adult homeostasis.
Fig. 2: Stem cell and stromal forces from tissue to cell scales drive morphogenesis of the gut.
Fig. 3: Epithelial cell–cell interactions constitute the molecular platforms for force transmission within the tissue.
Fig. 4: Cancer progenitors and CSCs mechanically sculpt their surrounding tissue to drive tumorigenesis and invasion.

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Acknowledgements

J.A. is a MacMillan Family Foundation Awardee of the Life Sciences Research Foundation. E.F. is a Howard Hughes Medical Investigator and is supported by grants from the NIH (R01-AR050452, R01-AR31737 and R37-AR27883), the Starr Foundation and the Stavros Niarchos Foundation.

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Author notes

  1. These authors contributed equally: Vincent F. Fiore, Jorge Almagro.

Authors and Affiliations

  1. Department of Immunology and Respiratory Diseases Research, Boehringer Ingelheim, Ridgefield, CT, USA

    Vincent F. Fiore

  2. Howard Hughes Medical Institute, Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY, USA

    Jorge Almagro & Elaine Fuchs

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  1. Vincent F. Fiore
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V.F.F. and J.A. performed literature research for the article. All authors discussed the content and wrote the manuscript.

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Glossary

Anchor cell

A specialized cell involved in the development of the reproductive system in nematodes such as Caenorhabditis elegans.

Anthracycline

A type of chemotherapeutic agent that targets topoisomerase and causes DNA damage.

Basement membrane

A thin layer of specialized extracellular matrix that sustains epithelia and endothelia, demarcating epithelial–stromal boundaries; it constitutes an anchoring surface for basal epithelial cells to divide.

Caveolae

Organized, complex invaginations of the plasma membrane.

Convergent extension

The narrowing and elongation of certain tissues during embryonic development.

Desmosomes

Cell–cell junctions formed of keratins, cadherins, desmoplakins and plakoglobins.

D. melanogaster wing disc

An appendage of epidermal stem cell precursors of the wing.

Dorsal mesentery

A thin mesenchymal tissue that connects the intestines to the abdominal wall.

Epiboly

In developmental biology, the spreading of the ectoderm simultaneous to the positioning of endoderm and mesoderm inside the embryo.

Germband

Primary layer of cells during embryonic development.

Hemidesmosomes

Cell–basement membrane junctions formed by keratins, integrins, plectins, laminins and collagen.

HRAS G12V

A MAPK pathway hyperactivating oncogenic mutation frequent in skin carcinoma.

KRAS G12D

A MAPK pathway hyperactivating oncogenic mutation frequent in pancreatic and lung cancers.

Mechanotransduction

Integration of mechanical input into intracellular signalling.

Mesenchyme

Embryonic connective tissue formed mostly by mesodermal cells and extracellular matrix.

Mesothelium

Epithelium that surrounds the chest, abdominal and pelvic cavities.

Multipotent progenitor cells

Cells capable of differentiating into different cells of a particular lineage.

Oncogenic transformation

Genetic alteration that gives rise to a cancer cell.

Placode

A pancake-shaped thickening of the ectoderm layer in the formation of glands and hair follicles.

PyMT

Polyomavirus middle-T oncogene used in mouse genetics to induce mammary tumours.

Smoothened

Frizzled G protein-coupled receptor required for activation of the embryonic Hedgehog pathway.

Stroma

Cells and molecules in the connective tissue of an organ.

Suprabasal cells

Of the skin, differentiated keratinocytes over the basal (stem) layer.

Taxane

A type of chemotherapeutic agent that inhibits tubulin polymerization.

Tight junctions

Cell–cell junctions formed by claudins and occludins.

Tricellular junctions

Specialized cell–cell junctions at the apical side of three epithelial or endothelial cells.

Young’s modulus

Mechanical property of solid materials that measures stiffness when a force is applied lengthwise.

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Fiore, V.F., Almagro, J. & Fuchs, E. Shaping epithelial tissues by stem cell mechanics in development and cancer. Nat Rev Mol Cell Biol (2025). https://doi.org/10.1038/s41580-024-00821-0

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