The Naked Mole Rat Genome Resource: facilitating analyses of cancer and longevity-related adaptations

Motivation: The naked mole rat (Heterocephalus glaber) is an exceptionally long-lived and cancer-resistant rodent native to East Africa. Although its genome was previously sequenced, here we report a new assembly sequenced by us with substantially higher N50 values for scaffolds and contigs. Results: We analyzed the annotation of this new improved assembly and identified candidate genomic adaptations which may have contributed to the evolution of the naked mole rat’s extraordinary traits, including in regions of p53, and the hyaluronan receptors CD44 and HMMR (RHAMM). Furthermore, we developed a freely available web portal, the Naked Mole Rat Genome Resource (http://www.naked-mole-rat.org), featuring the data and results of our analysis, to assist researchers interested in the genome and genes of the naked mole rat, and also to facilitate further studies on this fascinating species. Availability and implementation: The Naked Mole Rat Genome Resource is freely available online at http://www.naked-mole-rat.org. This resource is open source and the source code is available at https://github.com/maglab/naked-mole-rat-portal. Contact: [email protected]

Lipidome determinants of maximal lifespan in mammals

Maximal lifespan of mammalian species, even if closely related, may differ more than 10-fold, however the nature of the mechanisms that determine this variability is unresolved. Here, we assess the relationship between maximal lifespan duration and concentrations of more than 20,000 lipid compounds, measured in 669 tissue samples from 6 tissues of 35 species representing three mammalian clades: primates, rodents and bats. We identify lipids associated with species’ longevity across the three clades, uncoupled from other parameters, such as basal metabolic rate, body size, or body temperature. These lipids clustered in specific lipid classes and pathways, and enzymes linked to them display signatures of greater stabilizing selection in long-living species, and cluster in functional groups related to signaling and protein-modification processes. These findings point towards the existence of defined molecular mechanisms underlying variation in maximal lifespan among mammals.The National Natural Science Foundation of China (grant 31420103920), Strategic Priority Research Program of the Chinese Academy of Sciences (grant XDB13010200), the National Natural Science Foundation of China (grant 91331203), the National One Thousand Foreign Experts Plan (grant WQ20123100078), the Bureau of International Cooperation, Chinese Academy of Sciences (grant GJHZ201313) and the Federal Targeted Program for Research and Development in Priority Areas of Advancement of the Russian Scientific and Technological Complex for 2014–2020 (the Ministry of Education and Science of the Russian Federation), grant № 14.615.21.0002, the Unique identifier of the agreement: RFMEFI61515×0002. Additional support was obtained from the European Research Council (advanced grant 294678 to GRL).http://www.nature.com/scientificreportsam2017Zoology and Entomolog

Adenoviral Vector Driven by a Minimal Rad51 Promoter Is Selective for p53-Deficient Tumor Cells

Background: The full length Rad51 promoter is highly active in cancer cells but not in normal cells. We therefore set out to assess whether we could confer this tumor-selectivity to an adenovirus vector. Methodology/Principal Findings: Expression of an adenovirally-vectored luciferase reporter gene from the Rad51 promoter was up to 50 fold higher in cancer cells than in normal cells. Further evaluations of a panel of truncated promoter mutants identified a 447 bp minimal core promoter element that retained the full tumor selectivity and transcriptional activity of the original promoter, in the context of an adenovirus vector. This core Rad51 promoter was highly active in cancer cells that lack functional p53, but less active in normal cells and in cancer cell lines with intact p53 function. Exogenous expression of p53 in a p53 null cell line strongly suppressed activity of the Rad51 core promoter, underscoring the selectivity of this promoter for p53-deficient cells. Follow-up experiments showed that the p53-dependent suppression of the Rad51 core promoter was mediated via an indirect, p300 coactivator dependent mechanism. Finally, transduction of target cells with an adenovirus vector encoding the thymidine kinase gene under transcriptional control of the Rad51 core promoter resulted in efficient killing of p53 defective cancer cells, but not of normal cells, upon addition of ganciclovir. Conclusions/Significance: Overall, these experiments demonstrated that a small core domain of the Rad51 promoter ca

Reuniting philosophy and science to advance cancer research

Cancers rely on multiple, heterogeneous processes at different scales, pertaining to many biomedical fields. Therefore, understanding cancer is necessarily an interdisciplinary task that requires placing specialised experimental and clinical research into a broader conceptual, theoretical, and methodological framework. Without such a framework, oncology will collect piecemeal results, with scant dialogue between the different scientific communities studying cancer. We argue that one important way forward in service of a more successful dialogue is through greater integration of applied sciences (experimental and clinical) with conceptual and theoretical approaches, informed by philosophical methods. By way of illustration, we explore six central themes: (i) the role of mutations in cancer; (ii) the clonal evolution of cancer cells; (iii) the relationship between cancer and multicellularity; (iv) the tumour microenvironment; (v) the immune system; and (vi) stem cells. In each case, we examine open questions in the scientific literature through a philosophical methodology and show the benefit of such a synergy for the scientific and medical understanding of cancer

Comparative biology of longevity: the molecular mechanisms promoting long lifespan in the naked mole-rat (Heterocephalus glaber)

Thesis (Ph. D.)--University of Rochester. Dept. of Biology, 2013.This thesis addresses the proximal molecular mechanisms responsible for the longevity of the naked mole-rat (Heterocephalus glaber, hereafter NMR) compared to the short-lived laboratory mouse. One major contributor to short lifespan in the mouse is susceptibility to oncogenesis relative to other mammals. In contrast, the NMR is highly resistant to neoplasia. I describe work done in collaboration with Dr. Christopher Hine and Xiao Tian showing that high molecular weight hyaluronan is an important anti-tumor defense in the NMR. We use both in vitro and in vivo approaches to show that hyaluronan loss is necessary for transformation of NMR fibroblasts. Additionally, I characterized the NMR INK4a/b tumor suppressor locus. Normally, INK4a/b produces three tumor-suppressor proteins: p16INK4a, p15INK4b, and ARF. I show that the NMR additionally produces a splice variant that joins E1 from INK4b to E2 from INK4a. I confirmed expression of this variant in tissue culture and in vivo. I demonstrate that it is upregulated by hyaluronan and downregulated after hyaluronidase treatment. Overexpression of the variant confirmed it had biological activity similar to p16INK4a, which may contribute to NMR tumor resistance and longevity. NMR cells are exceptionally slow-growing compared to other rodent cell lines, even in optimal (physiological) tissue culture conditions. We detected an unusual ribosomal break in the NMR, and this led us to assay ribosomal translation rate. I constructed translational fidelity reporter plasmids, which were used to assay the accuracy of the NMR ribosome. We found that NMR cells had a similar overall translation rate as mouse cells, but their translational fidelity was four-fold higher. We propose that higher translational fidelity contributes to the lifespan of the NMR. Lastly, I compared the expression of IGF1R protein (a conserved regulator of lifespan from worms to humans) in a variety of tissues from all rodents available in our lab. I identified a strong inverse correlation between the level of expression of IGF1R in the brain tissue of rodents and their maximum lifespan. This correlation was maintained after phylogenetic correction using independent contrasts. This supports the idea that neuroendocrine signaling contributes to maximum lifespan of long-lived rodents