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Cell competition in development, homeostasis and cancer

Nature Reviews Molecular Cell Biology volume 24, pages 221–236 (2023)Cite this article

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Abstract

Organ development and homeostasis involve dynamic interactions between individual cells that collectively regulate tissue architecture and function. To ensure the highest tissue fidelity, equally fit cell populations are continuously renewed by stochastic replacement events, while cells perceived as less fit are actively removed by their fitter counterparts. This renewal is mediated by surveillance mechanisms that are collectively known as cell competition. Recent studies have revealed that cell competition has roles in most, if not all, developing and adult tissues. They have also established that cell competition functions both as a tumour-suppressive mechanism and as a tumour-promoting mechanism, thereby critically influencing cancer initiation and development. This Review discusses the latest insights into the mechanisms of cell competition and its different roles during embryonic development, homeostasis and cancer.

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Fig. 1: The types of cell competition.
Fig. 2: General modes of active cell competition.
Fig. 3: Cell competition during embryonic development.
Fig. 4: Cell competition in regulating the architecture and homeostasis of different tissue types.
Fig. 5: Clonal competition in the murine oesophagus.
Fig. 6: Expansion of mutant intestinal stem cells within and beyond the intestinal crypt.
Fig. 7: Cell competition in established cancers.

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Acknowledgements

S.M.v.N. is supported by ZonMw (Rubicon 452021320) and an EMBO Postdoctoral Fellowship (122-2022, non-stipendiary). This work is supported by Oncode Institute, the New York Stem Cell Foundation and grants from the European Research Council (ERG-CoG 101045612 - NIMICRY) and ZonMw (Vici 09-15018-21-10029) to L.V. L.V. is a New York Stem Cell Foundation–Robertson Stem Cell Investigator. The authors thank the members of the Laboratory for Experimental Oncology and Radiobiology for insightful discussions and comments on a draft of this work.

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Authors and Affiliations

  1. Amsterdam UMC, University of Amsterdam, Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam, Netherlands

    Sanne M. van Neerven & Louis Vermeulen

  2. Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, Netherlands

    Sanne M. van Neerven & Louis Vermeulen

  3. Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, Amsterdam, Netherlands

    Sanne M. van Neerven & Louis Vermeulen

  4. Oncode Institute, Amsterdam, Netherlands

    Sanne M. van Neerven & Louis Vermeulen

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  1. Sanne M. van Neerven
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Correspondence to Louis Vermeulen.

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L.V. received consultancy fees from Bayer, MSD, Genentech, Servier, and Pierre Fabre, but these had no relation to the content of this publication. S.M.v.N. declares no competing interests.

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Glossary

Fitness

On a cellular level, the relative ability of a cell to remain within a population of cells. On a population level, the relative ability of a clone or genetic variant to remain or expand within a tissue or organism.

Wing disc

A tissue carrying a small number of undifferentiated precursor cells that expand, differentiate and together form the adult wing and most of the notum in Drosophila melanogaster. Wing disc development is a key model to study cell competition.

Hippo signalling

An evolutionarily conserved pathway that controls organ size during development and homeostasis by regulating proliferation, differentiation and cell survival. Hippo signalling is often dysregulated during cancer development, which facilitates tumour expansion.

Epiblast

The pluripotent lineage giving rise to the three germ line layers in a complex process of differentiation and cell fate specification.

Clones

A population of genetically identical cells derived from the same progenitor.

Tissue fixation

When an entire tissue is completely taken over (100%) by the progeny of a single cell or clone, this variant is permanently present in the tissue, also known as monoclonality.

Neutral drift

The spread of genetic variants without a selective advantage.

Terminal end buds

Highly proliferative structures at the end of a duct that drive the development of the mammary gland.

Biased drift

The spread of genetic variants with a selective advantage.

Entosis

A non-apoptotic cell death process in which a cell invades or is engulfed by another cell while still alive.

Live-cell extrusion

A process by which live cells are eliminated from tissues in regions with high cell density (crowding) to maintain optimal cell numbers in the tissue.

Notum

The dorsal portion of the fly thorax.

Scribble

A cell polarity gene that, when gene function is lost, confers a disadvantage on the recipient cell.

Major histocompatibility complex class I

A class of proteins expressed at the cell membrane involved in mediating cellular immunity.

Caspase

A family of proteases that facilitate apoptosis by cleaving cysteines from important cellular structures, thereby disassembling them.

mTOR

Mechanistic target of rapamycin, a kinase that forms a complex (complex 1 or complex 2) with other proteins that together regulate processes such as cell growth, motility and survival.

Crypt fixation

A form of tissue fixation, but in the context of intestinal stem cell dynamics. Crypt fixation occurs when all the cells in a crypt are derived from the progeny of a single intestinal stem cell.

Paneth cells

Secretory epithelial cell type residing in the intestinal crypt bottom, providing important growth factors to support intestinal stem cell function.

Basement membrane

A thin layer of extracellular matrix that supports and signals with the epithelial cells that reside on top of it.

Hemidesmosome

A protein complex that enables stable adherence of epithelial cells to the basement membrane.

Cancer driver genes

A set of genes that when mutated result in a growth advantage that drives tumour formation.

WHIM syndrome

Congenital immune deficiency characterized by warts, hypogammaglobulinaemia, infections and myelokathexis, caused by mutations in the CXCR4 gene.

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van Neerven, S.M., Vermeulen, L. Cell competition in development, homeostasis and cancer. Nat Rev Mol Cell Biol 24, 221–236 (2023). https://doi.org/10.1038/s41580-022-00538-y

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