At Oxcitas we are studying the subterranean blind mole rat (Spalax) with the goal of developing novel therapeutic interventions that can assist in the fight against cancer and other age-related diseases. Spalax possess several unique traits which make them particularly important models for study in this area. Notably, Spalax display extraordinarily long lifespans exceeding 20 years compared to the 4-5 years achieved by laboratory rats.  Moreover, Spalax are able to tolerate extreme hypoxia (~3% O2 for around 14 hours) and high levels of oxidative stress. Most remarkably of all Spalax are highly resistant to the development of spontaneous tumours, and not once has one been observed in over 50 years of research.

Those few studies that have been published to date focusing on these traits within long-lived mole rat species have focused on the naked mole rat (Heterocephalus glaber). Heterocephalus glaber share similar features with Spalax, including an elevated resistance to cancer. For the most part the anticancer mechanisms employed by naked mole rats remain relatively unknown. One recent study suggested that high molecular mass hyaluronic acid (HMM-HA) secreted by their fibroblasts supported early contact inhibition preventing malignant transformation [1]. Naked mole rat fibroblasts have significantly elevated translational fidelity that stems from an alteration in ribosomal structure which may contribute to its cancer resistance [2]. However, further investigation of these mechanisms, in addition to the exploration of other potential factors, are required as it is unlikely that any single factor is able to account for these abilities.

Undoubtedly mole rats present a unique opportunity to decipher naturally evolved mechanisms of cancer resistance, which can inform the development of novel therapeutic interventions. Importantly, the lesser known Spalax offers advantages over the more widely studied naked mole rat. Spalax are often subjected to extreme conditions that are difficult to simulate in laboratory settings, including hypoxia. Therefore, Spalax are not bred in captivity and any observed traits are naturally occurring as their genetically encoded mechanisms evolved freely from artificial selection. Our initial research suggests that the blind and naked mole rats employ distinct mechanisms in their cancer resistance, ensuring the study of both species remains salient.

At Oxcitas we are using the latest developments in machine learning, artificial intelligence and computational biology to unravel the mechanisms behind the ageing process and have an impact in human longevity. Our proprietary drug discovery platform combines atomic level physicochemical interactions to clinically assessed risk measures, to provide an integrated solution.Through state-of-the-art in silico modelling and analytic techniques, our mission is to identify specific biomarker signatures of ageing to inform dew drug and novel targets.

• Hypoxia inducible factor1-alpha (HIF1α), erythropoietin (EPO), and EPO receptors are differentially expressed in Spalax compared to other rodents [3].

• Vascular endothelial growth factor (VEGF) a potent angiogenic factor is constitutively expressed at maximal levels in Spalax muscle, although its concentration does change under hypoxic conditions [4].

• Spalax has been shown to have higher levels of reactive oxygen species (ROS) processing enzymes compared to hypoxia-intolerant rodents [5]. There are constitutively higher transcript levels of antioxidant genes and their transcription factor Nrf2 in Spalax tissue as compared to rat [5]. Moreover, Spalax Nrf2 possesses several unique amino acid changes that are critical for its stability and transcriptional activity [5].

• Hypoxia induces genome-wide changes in transcript abundance of a remarkably large number of genes associated with apoptotic regulation, including anti-apoptotic response and cancer-related genes, in Spalax brain and muscle tissues [6].

• Spalax p53 harbours a substitution in the DNA-binding site, identical to mutations seen in human tumours which often inactivates p53 function [7]. However in Spalax this mutation abrogates the transcription of apoptosis genes and enhances the expression of genes involved in cell cycle arrest/DNA repair [7].

• Spalax possess a unique heparanase splice variant which lacks enzymatic activity and inhibits extracellular matrix degradation, tumour growth and metastasis [8].

• Spalax were also found to be highly resistant to chemically-induced tumorigenesis following exposure to both 3-MCA and DMBA/TCA while all similarly treated mice and rats developed the expected tumours [9].

• Fibroblasts isolated from Spalax have been found to secrete substances that are capable of inducing senescence and apoptosis in tumour cells [9].

• Spalax adipose derived stem cells (ADSCs) display a lower ability to migrate and penetrate tumours compared to rat ADSCs. Moreover, Spalax ADSCs have been observed to less readily differentiate into epithelial cells and incorporate into newly formed intra-tumoural vessels [10].

References

[1]     Tian X, Azpurua J, Hine C, et al. High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature. 2013;499:346–349.

[2]     Azpurua J, Ke Z, Chen IX, et al. Naked mole-rat has increased translational fidelity compared with the mouse, as well as a unique 28S ribosomal RNA cleavage. Proc. Natl. Acad. Sci. U. S. A. 2013;110:17350–17355.

[3]     Shams I, Nevo E, Avivi A. Ontogenetic expression of erythropoietin and hypoxia-inducible factor-1 alpha genes in subterranean blind mole rats. FASEB J.  Off. Publ. Fed. Am. Soc.  Exp. Biol. 2005;19:307–309.

[4]     Avivi A, Resnick MB, Nevo E, et al. Adaptive hypoxic tolerance in the subterranean mole rat Spalax ehrenbergi: the role of vascular endothelial growth factor. FEBS Lett. 1999;452:133–140.

[5]     Schulke S, Dreidax D, Malik A, et al. Living with stress: regulation of antioxidant defense genes in the subterranean,  hypoxia-tolerant mole rat, Spalax. Gene. 2012;500:199–206.

[6]     Malik A, Korol A, Weber M, et al. Transcriptome analysis of the spalax hypoxia survival response includes suppression of apoptosis and tight control of angiogenesis. BMC Genomics [Internet]. 2012;13:615. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3533650/.

[7]     Avivi A, Ashur-Fabian O, Joel A, et al. P53 in blind subterranean mole rats--loss-of-function versus gain-of-function activities on newly cloned Spalax target genes. Oncogene. 2007;26:2507–2512.

[8] Nasser NJ, Avivi A, Shafat I, et al. Alternatively spliced Spalax heparanase inhibits extracellular matrix degradation, tumor growth, and metastasis. Proc Natl Acad Sci U S A. 2009;106(7):2253–2258.

[9] Manov I, Hirsh M, Iancu T, et al. Pronounced cancer resistance in a subterranean rodent, the blind mole-rat, Spalax: In vivo and in vitro evidence. BMC Biol. 2013;11:91–102

[10] Mamchur A, Leman E, Salah S, et al. Adipose-Derived Stem Cells of Blind Mole Rat Spalax Exhibit Reduced Homing Ability: Molecular Mechanisms and Potential Role in Cancer Suppression. Stem Cells. 2018;36:1630–1642.