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Regulation of self-renewal and senescence in the DNA damaged tumour cells

Funding: Latvian Council of Science

Project number: 341/2012

Period: 2013-2016

Project manager: Dr.habil.med.J.Ērenpreisa

The project is aimed to study at the basic level of cell biology the cause of cancer relapse after genotoxic anticancer treatments. It is known that the two opposite processes result from these treatments: senescence (permanent cell division arrest) and self-renewal (cell division supporting immortality of tumour cells). The most recent information pioneered from the finding in our laboratory (Salmina et al., 2010) shows that genotoxic treatments do not select cancer stem cells but induce the stem-cell-like state in them and that this induction is associated with transition to illicit reversible polyploidy. This condition has a lot of peculiarities: shift of the DNA damage checkpoints, uncoupling from apoptosis, chromatin phenotypic plasticity and multi-potentiality. Our theoretical work suggested previously that this state is reached through the recapitulation of the primitive life-cycle program (Erenpreisa and Cragg 2007). That means that senescence should be a natural participant of this process. Our most recent data shows that the both responses are induced in the same tumour cells (Jackson et al., 2013). The questions for this project are as follows: how they co-exist, how the cell makes its choice, and how it can be influenced or prevented. From these positions, the relationship between two opposite processes will be investigated using several approaches: (1) the approach for study of the stochastic component of cell choice; (2) the means of acquisition and stabilization of the opposite phenotypes; (3) contribution of autophagy in competition between the two processes. As previously, the work will be carried out in collaboration with English and German colleagues. The efforts should result in one-two experimental articles and two reviews.

 

Salmina K, Jankevics E, Huna A, Perminov D, Radovica I, Klymenko T, Ivanov A, Jascenko E, Scherthan H, Cragg MS, Erenpreisa J. 2010. Up-regulation of the embryonic self-renewal network through reversible polyploidy in irradiated p53-mutant tumour cells.- Experimental Cell Research 316(13):2099-112.

Erenpreisa J., Cragg M. S. 2007. Cancer: a matter of life cycle? – Cell Biology International, 31(12):150 –1510.

Jackson TR, Salmina K, Huna A, Inashkina I, Jankevics E, Riekstina U, Kalnina Z, Ivanov A, Townsend PA, Cragg MS, Erenpreisa J 2013. DNA damage causes TP53-dependent coupling of self-renewal and senescence pathways in embryonal carcinoma cells.- Cell Cycle 12 (3):430-41.



Mājas lapas izstrādi finansēja ERAF 2.1.1.2. aktivitātes projekts Nr. 2010/0196/2DP/2.1.1.2.0/10/APIA/VIAA/004 "Latvijas biomedicīnas pētījumu integrācija Eiropas zinātnes telpā".