Departmental Seminar: “Evolutionary and molecular determinants of resistance to UV-induced skin cancer in naked mole rats” by Dr. Stan Avdieiev (Moffitt Cancer Institute)
January 21, 2021
4:00 PM - 5:00 PM
Evolutionary and molecular determinants of resistance to UV-induced skin cancer in naked mole rats
Stanislav Avdieiev1, Emily Vice2, Chris Whelan1, Joseph Kissil3, Robert A. Gatenby1, Elsa R. Flores1, Thomas Park2, Joel S. Brown1, Kenneth Y. Tsai1
1Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
2Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL, USA
3Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, USA
As unusually long-lived small mammals, naked mole-rats (NMR) should be and are, in fact, cancer resistant, but the mechanisms for both their longevity and low cancer incidence remain mysteries of considerable interest. As a species living as large colonies in extensive underground tunnel systems, they are under no direct selection to resist the mutagenic, tissue damaging and cancer causing effects of UV-radiation, an established complete carcinogen. We tested for this vulnerability by exposing NMR and mice to chronic low-dose UV for three months using a protocol that we routinely use to generate cutaneous squamous cell carcinoma in mice. Whereas all of the mice developed multiple tumors, the NMR developed no discernable lesions over the subsequent 18 months. Our subsequent analysis of the acute UV stress response in-vivo revealed 6-8 times the density of keratinocytes able to proliferate and replace dead, damaged or sloughed epidermal cells. The canonical TP53 response was markedly delayed in NMR and there was a near absence of epidermal apoptosis. GSEA pathway analysis revealed that NMR upregulate key metabolic pathways, with concomitant downregulation of DNA repair pathways and cell cycle checkpoints.
The dramatic failure to induce skin cancer suggests that NMR have general tumor-suppressor mechanisms that work in all tissues including against UV induced damage. Rather than triaging damaged cells or repairing DNA damage, NMR suppress cancer initiation and aging by maintaining unusually large numbers of progenitor cells, and by a cell metabolism that emphasizes cell longevity over cell replacement. Both processes obviate the need for long runs of cell divisions thereby suppressing the opportunity for cancer initiation or the expansion of a nascent tumor. Such mechanisms can explain why implantation or occurrence of genetically modified oncogenic cells in naked mole-rats fail to create malignancies, and provide a joint explanation for the lack of cancer and aging in naked mole-rats.
For zoom details, email Emily Beaufort (ebeauf2@uic.edu)
Date posted
Jan 12, 2021
Date updated
Jan 15, 2021