An Autochthonous Model of Lung Cancer Identifies Requirements for Cellular Transformation in the Naked Mole Rat

Abstract 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