African spiny mice show resistance to DMBA/TPA-induced squamous carcinogenesis with distinct benign tumor profile
image: Tumor resistance in African spiny mice is mediated by enhanced immune response to oncogenic stimuli, higher apoptosis, cell cycle arrest, and inhibition of Wnt/β-catenin signaling.
Credit: Fathima Athar, Francesco Morandini, Iqra Fatima, Isabella Silvestri, Seijoong Brian Kim, Minseon Lee, Xiaoyan Liao, Andrei Sharov, Vladimir Botchkarev, Andrei Seluanov, Vera Gorbunova
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:
- 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.
- 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.
- 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.
- 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).