Mount Sinai researchers found that p53-deficient skin cells in mice spread by organizing Wnt signaling into a radial gradient that keeps their progenitors self-renewing, rather than by dividing faster.

Long before a tumor forms, normal-looking tissue can harbor patches of mutant cells. As people age, their skin, esophagus and other tissues become a patchwork of clones carrying mutations in cancer-related genes. Most of these clones never become cancer, but some expand and crowd out their healthy neighbors, a process that may set the stage for disease.

A study from the Icahn School of Medicine at Mount Sinai sheds light on how one of the most important of these mutations gives cells a competitive edge. Writing in Science, researchers report that when cells lose the tumor suppressor p53, they spread through normal skin tissue not by dividing faster, but by reorganizing a key growth signal into a spatial gradient.

Zhe Ying, an assistant professor of stem cell biology and regenerative medicine at Mount Sinai and the study’s senior author, said it is “not simply how much Wnt signaling is present that matters.” Rather, he said, “When p53 is lost, Wnt activity becomes organized into a persistent spatial gradient,” an arrangement that “allows the mutant population to continue expanding through otherwise normal tissue.”

The guardian of the genome

The p53 protein is often called the guardian of the genome. When cells suffer DNA damage or other stresses, p53 can halt cell division, trigger repair or instruct damaged cells to die. Mutations in the TP53 gene, which encodes p53, are the most common genetic alteration in human cancer, found in roughly half of all tumors.

Mutations in p53 are also common in normal tissue. Studies of sun-exposed skin and the esophagus in healthy adults have found that clones carrying p53 mutations can occupy a substantial fraction of the tissue, expanding over decades. Understanding why these clones outcompete normal cells could help explain the earliest steps toward cancer.

A shift in cell fate

To investigate, the team tracked clones of p53-deficient epithelial cells as they expanded in mouse skin. Epithelial tissues, which line the body’s surfaces, are constantly renewed by progenitor cells. Each time a progenitor divides, its daughters can either remain progenitors, keeping the ability to divide, or differentiate into specialized cells that eventually stop dividing and are shed.

In normal tissue, those two outcomes are balanced. The researchers found that p53-deficient clones expanded mainly because that balance shifted. Mutant progenitors were more likely to stay self-renewing and less likely to differentiate. They did not divide faster or die less often, two mechanisms often assumed to drive the expansion of cancer-prone cells.

Three genes and a gradient

To find out how p53 loss tipped the balance, the team analyzed gene expression and the sites where p53 binds DNA, imaged Wnt signaling at single-cell resolution and screened more than 1,000 candidate genes regulated by p53.

Wnt signaling is a pathway that helps control stem cell behavior and tissue growth throughout the body, and it is frequently overactive in cancers, particularly colorectal cancer. The researchers identified three genes directly regulated by p53, called Sfrp1, Lrp1 and Usp22, that normally help keep Wnt signaling in check.

Without p53, Wnt activity increased. But it did not simply rise everywhere. Instead, it formed a persistent radial gradient within each mutant clone, with lower activity at the clone’s edge and higher activity at its center.

That spatial pattern proved to be the key. Clones with the gradient expanded efficiently. Clones in which Wnt activity was elevated more uniformly expanded less, even when their overall Wnt activity was higher. When the researchers disrupted the gradient, p53-deficient cells lost much of their ability to outcompete neighboring normal cells.

Why geometry matters

The finding highlights a theme of growing interest in biology: that the spatial organization of signals, not just their strength, shapes how tissues behave. Developing embryos rely on gradients of signaling molecules to pattern tissues, telling cells where they are and what to become. The new work suggests that mutant cells may exploit similar principles to gain ground in adult tissue.

The study was led by Ying with Qiwen Gan, a postdoctoral fellow in his laboratory, and included collaborators at Fred Hutchinson Cancer Center in Seattle. It was funded by the National Cancer Institute, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute of Dental and Craniofacial Research, the U.S. Department of Defense and the American Cancer Society.

Toward early intervention

The results could eventually point to new strategies for preventing cancer. If disrupting the Wnt gradient limits the spread of p53-deficient cells, it might be possible to slow the expansion of mutant clones before they progress toward cancer.

There is a long way to go. The work was done in mouse skin, and it is not yet clear whether the same mechanism operates in human tissues or in other organs where p53-mutant clones are common. Many p53 mutations in human cancers also do more than simply remove the protein, and some give it new harmful functions, which could change how mutant cells behave.

Still, the study offers a new view of how a single genetic change can let cells quietly take over healthy tissue, not by growing out of control, but by changing the shape of the signals around them.

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Notes

1. “Loss of the tumor suppressor p53 generates a signaling gradient that drives epithelial clonal expansion.” Science, 2026.
2. The Mount Sinai Hospital / Mount Sinai School of Medicine. “Mount Sinai study uncovers how loss of the critical tumor suppressor p53 enables mutant cells to expand through normal tissue.” EurekAlert!, 1 October 2026. https://www.eurekalert.org/news-releases/1146098.