A study of genes controlling carcinogenesis in a regenerative model flatworm Macrostomum lignano

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Kitill Ustyantsev1, Valeriya Vavilova2, Mikhail Biryukov3, Eugene Berezikov4
1Sector of molecular-genetic mechanisms of regeneration ICG SB RAS Novosibirsk, Russia, ustyantsev@bionet.nsc.ru
2Sector of molecular-genetic mechanisms of regeneration ICG SB RAS Novosibirsk, Russia, valeriya-vavilova@bionet.nsc.ru
3Interinstitutional laboratory of molecular paleogenetics and paleogenomics ICG SB RAS Novosibirsk, Russia, birykov@bionet.nsc.ru
4Sector of molecular-genetic mechanisms of regeneration ICG SB RAS Novosibirsk, Russia European Research Institute for the Biology of Ageing Groningen, The Netherlands, eberez@bionet.nsc.ru

В Free-living flatworm Macrostomum lignano is a novel model organism that provides a genetically tractable experimental system to specifically study the interplay between regulation of regeneration and cancer. Here, we tested two chemical carcinogens (MMS and CsA) and short wavelength ultraviolet irradiation (UVC) in M. lignano in order to identify genes and molecular pathways underlying carcinogenic response in this flatworms. For the first time, sensitivity of M. lignano to hard UV was evaluated, and it was shown that the worm can easily tolerate sterilization-level doses of higher than 100 mJ/cm2. Using differential gene expression analysis based on generated RNA-Seq data, common and individual patterns of M. lignano transcriptional response to the induced carcinogenesis by the tested stimuli were determined. This allowed us to select promising candidate genes for functional studies using RNAi knock-down screens and for determination of their role in stem cells regulation under regeneration and homeostasis in M. lignano.

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Yana Sizentsova
Yana Sizentsova
1 year ago

Dear Kirill, i have a few questions for you. First, what average lifespan of flatworms, including M. lignano? Are you sure that M. lignano is an appropriate model to study interplay between cancer and regeneration? Perhaps, the life of M. lignano is so short that its normal cells have no time to turn into malignant cells. And, the second question, how top 23 genes are regulated(up or down) in response to carcinogenic agents in human? Which of these genes do you find the most interesting for further research and why?

Kirill Ustyantsev
Kirill Ustyantsev
1 year ago

Dear Yana, thank you for your question!
M. lignano can live up to 2 years in the laboratory (and even longer) and can sustain multiple sequential amputations with full regeneration (https://onlinelibrary.wiley.com/doi/full/10.1111/acel.12739). There can be different types of malignancies: age-related, external factors related, and internal factors related (genetics, de novo mutations during embryogenesis). We do not claim it to be a model for the age-related cancer. But induced carcinogenesis is a different thing. There were studies in planaria which showed tumor outgrowth when the animal is exposed to chemical carcinogens and other toxic compounds. The second question here, how flatworms which can regenerate their body numerous times and have intrinsic population of dividing stem cells (neoblasts) which replenish every cell type would deal with externally induced carcinogenic factors. So, later different chemical compounds and/or physical treatments can be tested in mass on M. lignano which would be much cheaper for preliminar screens than with mouse and other models.

As for your second question, we did not check how the selected genes are regulated in human so far, since we are now doing functional molecular validations of the targets on the worm. Not all of the genes identified are conserved between flatworms and humans. And we, actually, find flatworm-specific genes more interesting for further study as they can provide an additional complementary fundamental knowledge on malignant prolifiration control which may be mislooked in other models.

Yana Sizentsova
Yana Sizentsova
1 year ago

Thank you for your very good answers! I have so much clarity. I agree flatworm-specific genes are more interesting for your study but suspect the most part of the genes are the genes with unknown functions and determine their role will not be so simple…Or isn’t this?

Kirill Ustyantsev
Kirill Ustyantsev
1 year ago

I would say, yes, indeed, but mostly for the detailed molecular description. But I do not thinks this is such a big problem for a functional screen. Gladly, M. lignano has enough useful features as a model to dissect a gene function in details: transgenesis, RNAi, in situ, antibodies and so on. Usually, RNAi screen provides good readouts, as the worm is transparent and you can easily see its organs, and that any abnormality during regeneration can be easily noticed too.