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. Herein, 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 protein using CRISPR-mediated genome editing. Whereas 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 to those present in human cells.