Key Points
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Lineage tracing in transgenic mice allows the study of stem, progenitor and cancer cells in their native environment and can give quantitative insight into cell behaviour. Experiments have two essential components: an inducible genetic switch, such as Cre recombinase, that activates the expression of the second essential component, the reporter gene, which allows the behaviour of cells to be followed.
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Each lineage tracing system requires characterization to define the properties of the cell subpopulation being followed. Quantifying cell behaviour requires stringent controls and large-scale data sets.
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Quantitative single cell lineage tracing has revealed cell behaviour in homeostatic epithelial tissues, such as the skin, oesophagus and intestine.
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The squamous epithelia of the skin and oesophagus are maintained by a single progenitor cell population that generates progenitor and differentiated cells to achieve homeostasis. The epidermis contains quiescent stem cells but the oesophageal epithelium does not.
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Intestinal epithelium is maintained by cycling stem cells expressing Lgr5 that reside in their niche at the base of the crypt. The restricted size of the niche is key in maintaining homeostasis.
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Oncogenes disrupt the balance between proliferation and differentiation in epithelial progenitors. For example, TP53-mutant cells in ultraviolet (UV)-exposed epidermis generate an excess of proliferating daughter cells, resulting in exponential expansion of mutant clones.
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Preliminary studies in benign tumours reveal that intestinal adenomas are sustained by a population of Lgr5-expressing cells that have escaped the niche, and in epidermal papillomas stem and progenitor cells proliferate in a manner that is reminiscent of wound healing.
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Lineage tracing in malignant lesions is more challenging owing to heterogeneity within and between tumours, but has already revealed unexpected early invasion and metastasis in pancreatic cancer models.
Abstract
For tumours to develop, mutations must disrupt tissue homeostasis in favour of deregulated proliferation. Genetic lineage tracing has uncovered the behaviour of proliferating cells that underpins the maintenance of epithelial tissues and the barriers that are broken in neoplastic transformation. In this Review, we focus on new insights revealed by quantifying the behaviour of normal, preneoplastic and tumour cells in epithelia in transgenic mice and consider their potential importance in humans.
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Acknowledgements
The authors thank D. Doupé, K. Jensen, A. Klein, K. Murai, A. Roshan, B. Simons and D.Winton for illuminating discussions.
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Alcolea, M., Jones, P. Tracking cells in their native habitat: lineage tracing in epithelial neoplasia. Nat Rev Cancer 13, 161–171 (2013). https://doi.org/10.1038/nrc3460
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