Genome stability in potentially immortal planarian stem cells

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Published: 27 Apr 2017
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Sounak Sahu - University of Oxford, Oxford, UK

Sounak Sahu speaks with ecancer at the 1st Cancer Research @ Bath Symposium about the use of planarian worms as a model of stem cell stability under DNA damage.

Planarian worms, which can be cut into over 100 pieces which will each regenerate into a whole worm, can resist significant amounts of ionising radiation, and their management of DNA repair pathways are of clinical interest alongside their telomeric maintenance.

Sahu considers other animal models with similar radioresistance, and considers how identifying genes involved in the pluripotency of adult stem cells could lead to further research. 

We work on planarians and planarians are fresh water flatworms that have been widely studied over the years as a model for regeneration. So if you cut the planarians into two halves each of these individual halves can regenerate back to an entire organism. That’s because they have these stem cells that are collectively pluripotent and that mediates this regeneration. I’m especially interested in the genome entrance mechanism in these adult stem cells in these flatworms and that’s the presentation I gave here today.
We use ionising radiation to induce DNA breaks and that’s what people use for radiotherapy to treat cancer and everything. In these adult stem cells we are interested in how these planarian stem cells can repair DNA breaks induced by radiation and whether we can find any novel DNA damage response chains that are involved in maintaining DNA damage and for genome stability. One interesting thing is planarians are very unique in resisting a high dose of ionising radiation so if we can know the mechanism how they can resist such a high dose then we can use it for improving radiotherapy and other cancers, for treating cancer and other diseases.
Have there been any pathways confirmed as significant?
We have not yet done that experiment, we have screened all the different DNA repair pathways and we use our radiation dose to see whether that has any effect. We have found conserved DNA repair genes like non-homologous enjoining or homologous recombination or the alternative non-homologous enjoining, how they repair those stranded of breaks, how they repair single stranded breaks, that’s what we know. We have screened all the canonical DNA repair genes but we have not found any healing pathways which we are still looking for.
Why use planarian as a model?
That’s because they have these adult stem cells and they are also radiation resistant. Very few modal systems are radio-resistant, like bacteria, like tardigrades, but they don’t have an adult stem cell and that’s where we are utilising the pluripotent stem cell in planarians to understand radiation effect on these stem cells so that we can use it for improving radiotherapy to target cancer stem cells.
Is this similar to the radiation resistance of naked mole rats?
It is interesting because both naked mole rates, compared to other rodents they are quite long-lived, they live for 23 years and show negligible signs of aging compared to other rodents. Similarly planarians are also long-lived because we just serially amputate the worms and they keep on regenerating throughout their life and they show negligible or no signs of aging. That also imposes the question that they should have a strong genome maintenance mechanism in order for these stem cells to keep repopulating over time and to regenerate over multiple generations.
Will you be going into trials?
If we find some unique chains, that they are upregulating something we can think of like tardigrades, like very recently they have shown DNA repair genes getting upregulated and that protects the tardigrades’ DNA from a high dose of ionising radiation, if we find a unique gene like that we can use that like drug targets for chemotherapy and radiotherapy later on.
Was there any interesting discussion generated?
There are some questions that they asked about mutational hotspots. We have no idea whether there is like with radiation in the genome there are mutation hotspots or not. For that we may have to do a whole genome sequencing after radiation and when they have repopulated to find if these hotspots are there or not. Whereas of now we don’t know anything.