Skin regeneration underlies cancer resistance in Acomys

Abstract Cancer and regeneration share common characteristics, including cell dedifferentiation, proliferation, migration, and immune cell activation. These processes proceed, however, during tumorigenesis without the strict control exhibited during regeneration4. Most common in animals without an advanced adaptive immune system, regeneration is not widespread in mammals. The Spiny Mouse (Acomys spp.) is a notable exception, possessing the unique ability to regenerate large wounds in the skin, ear, and other complex organs completely and without the presence of scar tissue. Here, we employ Acomys to test the hypothesis that enhanced mammalian regeneration significantly alters cancer incidence and/or initiation compared to the non-regenerative laboratory mouse (Mus musculus). We found that Acomys has drastically reduced tumor incidence and increased survival following chemical carcinogenesis compared to Mus, despite a prolonged exposure period. Acomys undergoes a regenerative response including widespread cell death and increased epithelial cell proliferation in response to chemical carcinogenesis. During this process, we identify a subset of treatment-dependent Tenascin C (Tnc)-expressing regenerative fibroblasts and Tumor necrosis factor (Tnf) expressing T cells as the likely drivers of regeneration. Finally, we found that Erk phosphorylation, a key molecular mechanism of tissue regeneration in Acomys, is a significant mediator of epidermal cell death following carcinogenesis. These findings establish a new perspective on cancer initiation and the mechanistic link between tissue regeneration and intrinsic cancer resistance.