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Grajzel Dániel

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Grajzer Dániel
In hierarchical tissues small compartments lead to a selective threshold below which mutations cannot persist

Aug 28 - szerda

13:30 – 15:30

II. Poszterszekció

P40

In hierarchical tissues small compartments lead to a selective threshold below which mutations cannot persist

Grajzel Dániel^1,3, Derényi Imre^1,2 és Szöllősi Gergely^1,3

¹ Eötvös Loránd Tudományegyetem, Biológiai Fizika Intézet

² MTA-ELTE Statisztikus és Biológiai Fizika Kutatócsoport

³ MTA-ELTE Lendület Evolúciós Genomika Kutatócsoport

Cancer is a genetic disease fuelled by somatic evolution. Hierarchical tissue organisation can slow somatic evolution by two qualitatively different mechanisms: by cell differentiation along the hierarchy ‘‘washing out’’ harmful mutations [1][2](Nowak 2003, Werner 2013) and by limiting the number of cell divisions required to maintain a tissue [3] (Derényi and Szöllősi 2017). Here we explore the effects of differences in compartment size on somatic evolution in hierarchical tissues by considering cell number regulation that acts on cell division rates such that the number of cells in the tissue has the tendency to return to its desired homeostatic value.

Introducing mutants with a proliferative advantage we demonstrate the existence of a third fundamental mechanism by which hierarchically organised tissues are able to slow down somatic evolution. We show that tissue size regulation in hierarchically organized tissues leads to the emergence of a threshold proliferative advantage, below which mutants cannot persist. We find that the most significant determinant of the threshold selective advantage is compartment size, with the threshold being higher the smaller the number of cells in the compartment.

Our results demonstrate that in sufficiently small compartments even mutations that confer substantial proliferative advantage cannot persist, but are expeled from the tissue by differentiation along the hierarchy. The resulting selective barrier can significantly slow down somatic evolution and reduce the risk of cancer by limiting the accumulation of mutations that increase the proliferation of cells.

Irodalom

[1] Nowak M, Michor F, Iwasa Y (2003) The linear process of somatic evolution. Proceedings of the National Academy of Sciences 100:14966-14969.

[2] Werner B, Dingli D, Traulsen A (2013) A deterministic model for the occurrence and dynamics of multiple mutations in hierarchically organized tissues. Journal of The Royal Society Interface 10:20130349-20130349.

[3] Derényi I, Szöllősi G (2017) Hierarchical tissue organization as a general mechanism to limit the accumulation of somatic mutations. Nature Communications 8:14545.

Szöllősi Gergely
Hierarchical tissues that minimize somatic evolution

Aug 28 - szerda

13:30 – 15:30

II. Poszterszekció

P42

Hierarchical tissues that minimize somatic evolution

Demeter Márton ² , Grajzel Dániel ² , Derényi Imre ¹ , Szöllősi Gergely ^1,2

¹ Biológiai Fizika Tanszék, ELTE

² MTA-ELTE “Lendület” Evolúciós Genomika Kcs.

Cancer development is a somatic evolutionary process where cells must divide and as a result mutations that can ultimately lead to neoplastic progression may accumulate. Hierarchically organized tissues can slow down somatic evolution by reducing the number of cell divisions along cell lineages thus limiting mutation accumulation [1] and by ”washing out” mutations even if they confer a proliferative advantage [2].

Here we explore the structure of hierarchical tissues that minimize somatic evolution. We derive the critical number of mutations, necessary for triggering neoplastic progression as a function of dynamical parameters of the hierarchy. Using this results we are able to analytically estimate the probability of neoplastic progression based on statistical characteristics of the cell-linage tree. We find a trade off between mutation accumulation and the proliferative disadvantage of cells in the hierarchy leading to an evolutionary optimum in the probability of neoplastic progression.

In particular we find that in tissues with physiologically realistic parameters the division rate of stem cells is higher than the extremely low rates required to minimize mutation accumulation [1]. The resulting optimum induced by selection is characterized by a relatively large number of stem cell divisions, with the consequence that the majority of the driver mutations can accumulate within stem cells.

References:

[1] Derenyi & Szollosi, Hierarchical tissue organization as a general mechanism to limit the accumulation of somatic mutations.

Nature Communications 2017

[2] Nowak, Michor, Isawa, The linear process of somatic evolution. PNAS 2003