The transcriptome landscape of the carcinogenic treatment response in the blind mole rat: Insights into cancer resistance mechanisms

Robert Altwasser, Arnon Paz, Abraham Korol, Irena Manov, Aaron Avivi, Imad Shams

Research output: Contribution to journalArticlepeer-review

Abstract

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 related to 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 microRNA targets. We also found higher levels of gene expression of some DNA repair pathways in Spalax than in 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 remodeling the extracellular matrix, the possible growth is limited, and the proliferation of cancer cells was potentially 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 showed a distinct expression pattern in untreated or tolerant Spalax compared to animals that developed a developed either a benign or malignant tumor. While further study is necessary, we believe that these genes may serve as candidate markers in cancer detection.

Original languageEnglish
Article number17
JournalBMC Genomics
Volume20
Issue number1
DOIs
StatePublished - 8 Jan 2019

Bibliographical note

Funding Information:
I.M. was supported by the Ministry of Immigrant Absorption and the Committee for Planning and Budgeting of the Council for Higher Education, Israel. We thank Dr. Vered Domankevich for valuable comments and suggestions. The authors also thank The Carver Biotechnology Center, headed by Dr. Mark Band, University of Illinois, for providing the sequencing services.

Funding Information:
This work was supported by John Templeton Foundation [grant #5305] and by the generous donation of the Kadas Family (UK). Funding bodies did not have a role in the design of the study and collection, analysis, and interpretation of data, neither in writing the manuscript.

Publisher Copyright:
© 2019 The Author(s).

Keywords

  • Cancer
  • Cancer-resistance
  • Extracellular matrix
  • Fanconi anemia
  • Spalax

ASJC Scopus subject areas

  • Biotechnology
  • Genetics

Fingerprint

Dive into the research topics of 'The transcriptome landscape of the carcinogenic treatment response in the blind mole rat: Insights into cancer resistance mechanisms'. Together they form a unique fingerprint.

Cite this