GSE117499
The transcriptome landscape of the carcinogenic treatment response in the blind mole rat: Insights into cancer resistance mechanisms [RNA-seq]
Background: Spalax, the blind mole rat, developed an extraordinary cancer resistance during 40 million years of evolution in a subterranean, hypoxic, thus DNA damaging, habitat. In 50 years of Spalax research, no spontaneous cancer development has been observed. The mechanisms underlying this resistance are still not clarified. We investigated the genetic difference between Spalax and mice that might enable the Spalax relative resistance to cancer development. We compared Spalax and mice responses to a treatment with the carcinogen 3-Methylcholantrene, as a model to assess Spalax' cancer-resistance. Results: We compared RNA-Seq data of untreated Spalax to Spalax with a tumor and identified a high number of differentially expressed genes. We filtered these genes by their expression in tolerant Spalax that resisted the 3MCA, and in mice, and found 25 genes with a consistent expression pattern in the samples susceptible to cancer among species. Contrasting the expressed genes in Spalax with benign granulomas to those in Spalax with malignant fibrosarcomas elucidated significant differences in several pathways, mainly the extracellular matrix and the immune system. We found a central cluster of ECM genes that differ greatly between conditions. Further analysis of these genes revealed potential drug targets and associated microRNAs.We also show that in Spalax has higher levels of gene expression of some DNA repair pathways than other murines, like the majority of Fanconi Anemia pathway. Conclusion: The comparison of the treated with the untreated tissue revealed a regulatory complex that might give an answer how Spalax is able to restrict the tumor growth. By strengthening the extracellular matrix, the possible growth is limited, and the proliferation of cancer cells was prevented. We hypothesize that this regulatory cluster plays a major role in the cancer resistance of Spalax.  Furthermore, we identified 25 additional candidate genes that show a distinct expression pattern in untreated or tolerant Spalax compared to animals that developed a growth, either benign or malignant. While further study is necessary, we believe that these genes may be used as markers in cancer detection. Overall design: 12 Spalax and 6 mice were used. Animals were treated with a single injection of 3MCA as follows: 200 µg/200 µl for mice; 1 mg/500 µl for Spalax. Animals used in this experiment were: six approximately 2-year-old Spalax individuals; six 10-year old or older Spalax individuals; six 3- to 4- month-old mice. Animals were observed once a week until tumors could be palpated, and then two to three times a week.