African spiny mice show resistance to DMBA/TPA-induced squamous carcinogenesis with distinct benign tumor profile [acomys_irrad]
African spiny mice, Acomys cahirinus (Acomys), is an emerging mammalian model for regeneration studies because of its ability to morphologically and functionally regenerate several tissues. However, as limited regenerative abilities in most mammals are viewed as an antitumor strategy, it is intriguing how Acomys balance regeneration and tumor suppression. To date, no spontaneous tumors have been reported in Acomys, suggesting it may be resistant to cancer. In this study, we use in vitro and in vivo approaches to investigate if A. cahirinus is susceptible to carcinogenesis. We report that, like mice, two oncogenic hits - activation of oncogenic RasG12V and inactivation of p53 or pRb - are sufficient to transform skin fibroblasts from A. cahirinus. However, surprisingly, active p53 dramatically reduces the tumor forming ability of the transformed fibroblasts.  In the DMBA/TPA treatment model of in vivo skin carcinogenesis with animals aged 1-1.5 years, C57BL/6 laboratory mice formed pre-malignant skin tumors in 22 weeks, while A. cahirinus did not show any effects. A longer TPA treatment period of 30 weeks induced benign sebaceous adenomas in A. cahirinus. This showed that A. cahirinus was resistant to squamous skin carcinogenesis typically induced by DMBA/TPA treatment. A. cahirinus showed significantly higher upregulation of immune response and differentially expressed tumor suppressors and oncogenes in DMBA/TPA-treated skin when compared to mice. Wnt/ß-catenin signaling, a major mediator of squamous carcinogenesis associated with DMBA/TPA treatment, was inhibited in A. cahirinus. Several Wnt/ß-catenin targets and effector transcription factors, especially Lef1, were transcriptionally downregulated in A. cahirinus. Overall, our study shows that A. cahirinus may be resistant to DMBA/TPA-induced squamous carcinogenesis, and this resistance may be mediated by a strong immune response and the inhibition of Wnt/ß-catenin signaling. Overall design: RNA-seq profiling of A. cahirinus, C56BL6 mouse, wild mouse fibroblasts 24h and 12d after 0 gy / 10 gy / 20 gy gamma irradiation