Rochelle Buffenstein

The naked mole-rat (Bathyergidae; Heterocephalus glaber ) is an extremophilic rodent that lives an extraordinarily long and healthy life despite having evolved in harsh, arid, underground conditions. This ~ 31-million-year evolutionary path and concomitant adaptations have surprisingly yielded a broad suite of cytoprotective mechanisms that have enabled them to avoid cancer. Compared to above-ground dwelling species, the incidence of spontaneous neoplasia in naked mole-rats is extremely low. Naked mole-rats also evade experimental induction of tumorigenesis by both chemical carcinogens and physical stressors, even though their cells can be transformed with high levels of oncogene exposure or transduced with additional oncogenes. While the exact blueprint that the naked mole-rat has evolved to provide this profound resistance to cancer remains elusive, it is clear that multiple genomic and molecular mechanisms are involved. These involve both cell autonomous and non-autonomous mechanisms and include a more cytoprotective intracellular environment, efficient DNA repair processes, a low abundance of tumor-promoting oncogenes, unique adaptations in several signaling pathways (e.g., Wnt pathways), greater reliance on highly responsive innate immune cells, dampened inflammatory responses to carcinogenic insults, an abundance of stable tumor suppressor genes (e.g., p53), and unique (e.g., INK4a mediated) cell death mechanisms. A circulating population of cytotoxic γδT cells provides an additional layer of protection against cancer development, progression and metastasis. A subset of these multifaceted mechanisms is shared with the muroid, subterranean-dwelling, cancer-resistant, Middle Eastern blind mole-rat (Nannospalax ehrenbergi ), suggesting that phylogenetically independent, convergent, evolutionary tinkering has contributed to their common cancer-resistant phenotype. Elucidating these multi-layered, disparate evolved mechanisms will provide valuable, translational insights into the critical components and protections of this devastating disease and may hopefully lead to novel therapeutics.

Antibody validation against NMR proteins

Sequence chromatograms assessing genomic cleavage using the first-generation Tp53 and Rb1 adenovirus.

Schematic of strategy to induce the EML4-ALK inversion

List of BaseScope probes used in study

Shows Co-localization of Eml4-Alk and Sftpc in NMR lung tumors.

Assessment of the effect of Eml4-Alk expression in NMR skin fibroblasts.

There is growing interest in understanding the mechanisms underlying differences in cancer incidence among species (comparative oncology). The naked mole rat (NMR) is often referenced as “cancer resistant” and prior studies focused on identifying mechanisms explaining this. However, efforts to assess this in vivo have been limited. In this study, we provide evidence that the NMR presents as a novel autochthonous model of lung tumor initiation, driven by an introduction of the oncogenic Eml4-Alk fusion gene using CRISPR-mediated genome editing. Although in mice, the inversion alone is sufficient to drive tumorigenesis, the inversion alone was insufficient to drive tumorigenesis in the NMR lung, and tumor development required additional losses of the tumor suppressors p53 and pRb. Our findings suggest that the proposed “resistance” of the NMR to the development of cancer may reflect that the genetic events leading to tumor initiation are likely to be comparable with those present in human cells.Significance:To identify evolutionary divergent mechanisms of cancer resistance, we assessed tumorigenesis in vivo using the NMR, a species considered to exhibit cancer resistance. Our findings suggest that the proposed “resistance” of NMRs to the development of cancer may reflect tumor initiation mechanisms comparable with the mechanisms present in humans.See related commentary by Boddy and Abegglen, p. 7

Genomic PCR analysis of Eml4-Alk infections.