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Epidermal Tissue Adapts to Restrain Progenitors Carrying Clonal p53 Mutations.

ABSTRACT: Aging human tissues, such as sun-exposed epidermis, accumulate a high burden of progenitor cells that carry oncogenic mutations. However, most progenitors carrying such mutations colonize and persist in normal tissue without forming tumors. Here, we investigated tissue-level constraints on clonal progenitor behavior by inducing a single-allele p53 mutation (Trp53R245W; p53?/wt), prevalent in normal human epidermis and squamous cell carcinoma, in transgenic mouse epidermis. p53?/wt progenitors initially outcompeted wild-type cells due to enhanced proliferation, but subsequently reverted toward normal dynamics and homeostasis. Physiological doses of UV light accelerated short-term expansion of p53?/wt clones, but their frequency decreased with protracted irradiation, possibly due to displacement by UV-induced mutant clones with higher competitive fitness. These results suggest multiple mechanisms restrain the proliferation of p53?/wt progenitors, thereby maintaining epidermal integrity.

SUBMITTER: Murai K

PROVIDER: S-EPMC6224607 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Epidermal Tissue Adapts to Restrain Progenitors Carrying Clonal p53 Mutations.

Murai Kasumi K Skrupskelyte Greta G Piedrafita Gabriel G Hall Michael M Kostiou Vasiliki V Ong Swee Hoe SH Nagy Tibor T Cagan Alex A Goulding David D Klein Allon M AM Hall Benjamin A BA Jones Philip H PH

Cell stem cell 20180927 5

Aging human tissues, such as sun-exposed epidermis, accumulate a high burden of progenitor cells that carry oncogenic mutations. However, most progenitors carrying such mutations colonize and persist in normal tissue without forming tumors. Here, we investigated tissue-level constraints on clonal progenitor behavior by inducing a single-allele p53 mutation (Trp53<sup>R245W</sup>; p53<sup>∗/wt</sup>), prevalent in normal human epidermis and squamous cell carcinoma, in transgenic mouse epidermis. ...[more]

PMID: 30269904

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Project description:Identification and characterization of mutations that drive cancer evolution constitute a major focus of cancer research. Consequently, dominant paradigms attribute the tumorigenic effects of carcinogens in general and ionizing radiation in particular to their direct mutagenic action on genetic loci encoding oncogenes and tumor suppressor genes. However, the effects of irradiation are not limited to genetic loci that encode oncogenes and tumor suppressors, as irradiation induces a multitude of other changes both in the cells and their microenvironment which could potentially affect the selective effects of some oncogenic mutations. P53 is a key tumor suppressor, the loss of which can provide resistance to multiple genotoxic stimuli, including irradiation. Given that p53 null animals develop T-cell lymphomas with high penetrance and that irradiation dramatically accelerates lymphoma development in p53 heterozygous mice, we hypothesized that increased selection for p53-deficient cells contributes to the causal link between irradiation and induction of lymphoid malignancies. We sought to determine whether ionizing irradiation selects for p53-deficient hematopoietic progenitors in vivo using mouse models. We found that p53 disruption does not provide a clear selective advantage within an unstressed hematopoietic system or in previously irradiated BM allowed to recover from irradiation. In contrast, upon irradiation p53 disruption confers a dramatic selective advantage, leading to long-term expansion of p53-deficient clones and to increased lymphoma development. Selection for cells with disrupted p53 appears to be attributable to several factors: protection from acute irradiation-induced ablation of progenitor cells, prevention of irradiation-induced loss of clonogenic capacity for stem and progenitor cells, improved long-term maintenance of progenitor cell fitness, and the disabling/elimination of competing p53 wild-type progenitors. These studies indicate that the carcinogenic effect of ionizing irradiation can in part be explained by increased selection for cells with p53 disruption, which protects progenitor cells both from immediate elimination and from long-term reductions in fitness following irradiation.

Dataset Information

Epidermal Tissue Adapts to Restrain Progenitors Carrying Clonal p53 Mutations.

Publications

Epidermal Tissue Adapts to Restrain Progenitors Carrying Clonal p53 Mutations.

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