Long term latency of highly mutated cells in normal mouse skin is reversed by exposure to tumor promoters and chronic tissue damage.

Historical studies performed nearly a century ago using mouse skin models identified two key steps in cancer evolution: initiation, a likely mutational event, and promotion, driven by inflammation and cell proliferation. Initiation was proposed to be permanent, with promotion as the critical rate-limiting step for cancer development. Here, we carried out whole genome sequencing to demonstrate that initiated cells with thousands of mutagen-induced mutations can persist for long periods and are not removed by cell competition or by immune intervention, thus mimicking the persistence of cells with cancer driver mutations in normal human tissues. In the mouse, these cells do not give rise to tumors unless exposed to the tumor promoter TPA. Tissue damage and regenerative proliferation, but not normal cell turnover, consistently trigger tumor formation. Wounding, promoter treatment, and obesity enhance promotion without increasing mutational burden, supporting the possibility of future cancer prevention efforts directed at promotional risk factors.