2026-10-01 マウントサイナイ医療システム(MSHS)
＜関連情報＞
- https://www.mountsinai.org/about/newsroom/2026/mount-sinai-study-uncovers-how-loss-of-the-critical-tumor-suppressor-p53-enables-mutant-cells-to-expand-through-normal-tissue
- https://www.science.org/doi/10.1126/science.aed3065
腫瘍抑制因子p53の喪失は、上皮クローン増殖を促進するシグナル勾配を生成する Loss of the tumor suppressor p53 generates a signaling gradient that drives epithelial clonal expansion
Qiwen Gan, Wei Li, Rachel K. Lex, Zhe Ying, and Slobodan Beronja
Science Published:1 Oct 2026
DOI:https://doi.org/10.1126/science.aed3065
Structured Abstract
INTRODUCTION
Normal tissues accumulate mutations throughout life, but most mutant cells remain contained. Loss of the tumor suppressor p53 is common in epithelial cancers and can allow mutant cell populations to occupy large areas of normal tissue. How p53 loss changes cell behavior to permit this expansion has remained unclear.
RATIONALE
We used mouse skin as a model to determine how p53 restrains the growth of epithelial clones. By combining lineage tracing with quantitative analysis of daughter cell fate, we found that p53 loss drives clonal expansion by enlarging the basal progenitor population rather than by disabling canonical cytostatic pathways. This observation led us to identify direct p53 targets that govern progenitor renewal and differentiation through a combination of gene expression and chromatin analyses, large-scale in vivo genetic screens, and single-cell imaging of Wnt activity.
RESULTS
Loss of p53 shifted epidermal progenitor cells toward self-renewal and away from differentiation, allowing the progenitor pool to expand over successive cell divisions. A p53 variant that cannot activate cell cycle arrest, senescence, and cell death programs still restrained progenitor renewal, indicating that noncanonical p53 targets suppress clonal expansion.
By integrating transcriptional profiling, p53 binding maps, and functional screening in mouse epidermis, we identified three direct p53 targets—secreted frizzled-related protein 1 (Sfrp1), low-density lipoprotein receptor–related protein 1 (Lrp1), and ubiquitin-specific peptidase 22 (Usp22)—that act as the most genetically upstream regulators of the p53-governed differentiation and renewal network. These three regulators suppress Wnt signaling at both the ligand and intracellular levels, and upon p53 inactivation, their expression was reduced and Wnt activity increased. Owing to the multilevel nature of Wnt suppression, increase in Wnt activity across the p53-deficient clones was not uniform; it was lowest at the edge of the clones and rose progressively toward their centers, creating a radial gradient that persisted across different stages of clonal expansion regardless of clonal density.
Genetic experiments that manipulated the pattern of Wnt activity showed that gradient Wnt activation was associated with robust clonal expansion. Additional manipulations that produced uniformly elevated Wnt activity, including conditions where average Wnt activity was higher than in p53-deficient clones, resulted in clones that expanded more slowly.
CONCLUSION
p53 restrains epithelial colonization by maintaining a network that controls both the strength and spatial organization of Wnt signaling. Its loss creates a radial Wnt activity gradient that is associated with sustained progenitor self-renewal and rapid clonal expansion. These findings show that the spatial pattern of a growth signal, not only its overall level, can determine how mutant cells spread through normal tissue.
Spatial organization of Wnt signaling after p53 loss.
In normal epidermis, p53 maintains expression of several Wnt suppressors and balances progenitor renewal with differentiation. Loss of p53 weakens this network, producing a radial increase in Wnt activity from the clone edge toward its center. The resulting gradient supports sustained progenitor renewal and rapid expansion through the surrounding tissue.
Abstract
Although tumor protein p53 (TP53) mutations are among the most common lesions in epithelial cancers, how p53 loss drives unrestrained clonal expansion remains unclear. Working with mouse epidermis, we found that p53 suppresses clonal expansion by limiting progenitor self-renewal. Integrating chromatin immunoprecipitation sequencing, transcriptional analyses, and genetic screens, we identified a p53-dependent network controlling progenitor renewal and differentiation, in which secreted frizzled-related protein 1 (Sfrp1), low-density lipoprotein receptor–related protein 1 (Lrp1), and ubiquitin-specific peptidase 22 (Usp22) were direct targets of p53 and the most genetically upstream components. Their suppression after p53 loss generated a radial gradient of Wnt activity across mutant clones. Genetic manipulation showed that a Wnt activity gradient, rather than uniform elevation, was associated with sustained clonal expansion. These findings identify spatial organization as a determinant of clonal behavior and a mechanism by which TP53 inactivation drives tissue colonization.
