The main text describes the experimental design, including the generation of transformed Acomys fibroblasts, xenograft assays, and the two-stage chemical carcinogenesis model using DMBA/TPA. It details the results of these experiments, showing that while Acomys fibroblasts require the same number of oncogenic hits for transformation as mouse cells, in vivo, they are resistant to DMBA/TPA-induced carcinogenesis. The study further explores the underlying mechanisms, such as cell cycle arrest, apoptosis, immune response, and Wnt/β-catenin signaling, through transcriptomic analysis and immunohistochemistry.
Key findings from the study include:

1. Resistance to Carcinogenesis: Acomys showed significant resistance to DMBA/TPA-induced skin carcinogenesis compared to C57BL/6 mice, with delayed tumor formation and a benign tumor profile (sebaceous adenomas) instead of malignant squamous cell carcinomas.
2. Enhanced Immune Response: Acomys exhibited a stronger immune response to DMBA/TPA treatment, characterized by higher infiltration of T cells and macrophages compared to C57BL/6 mice. This heightened immune response likely contributes to their resistance to tumorigenesis.
3. Higher Apoptosis and Cell Cycle Arrest: Acomys fibroblasts showed efficient cell cycle arrest and higher levels of apoptosis in response to γ-radiation and DMBA/TPA treatment, indicating a tighter control over cell proliferation and survival.
4. Inhibition of Wnt/β-Catenin Signaling: Wnt/β-catenin signaling, a major mediator of squamous carcinogenesis, was inhibited in Acomys upon DMBA/TPA treatment, in contrast to its upregulation in C57BL/6 mice. This inhibition likely contributes to the benign tumor profile observed in Acomys.

This study provides compelling evidence that Acomys exhibit resistance to DMBA/TPA-induced skin carcinogenesis, characterized by delayed tumor formation and a benign tumor profile. The resistance is attributed to a combination of cell-autonomous mechanisms, such as robust cell cycle arrest and apoptosis, and non-cell-autonomous mechanisms, including enhanced immune response and downregulation of Wnt/β-catenin signaling. These findings offer insights into naturally evolved anti-cancer mechanisms in regenerative mammals and suggest potential therapeutic targets for preventing tumor formation during regenerative therapies. The work entitled “ African spiny mice show resistance to DMBA/TPA-induced squamous carcinogenesis with distinct benign tumor profile” was published on Protein & Cell (published on Mar. 22, 2025).
DOI：https://doi.org/10.1093/procel/pwaf024