An autochthonous model of lung cancer in the Naked Mole-Rat (Heterocephalus glaber)

There is growing interest in understanding the mechanisms underlying differences in cancer incidence among species. 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. While 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 tumor initiation mechanisms that are likely to be comparable to the mechanisms present in human cells. We have utilized single cell RNA sequencing on lung tumors from NMRs. We infected NMRs with 3 different oncogeneic events thru CRISPR adenovirus and allowed tumors to form in the lungs. After 15 weeks, we harvested the lungs of 3 tumor-bearing NMRs and processed them for single cell RNA sequencing.