Összes szerző

Szöllősi Gergely

az alábbi absztraktok szerzői között szerepel:

Demeter Márton Csaba
The structure of hierarchical tissues that minimize somatic evolution

Aug 28 - szerda

13:30 – 15:30

II. Poszterszekció

P39

The structure of hierarchical tissues that minimize somatic evolution 

Demeter Márton Csaba¹, Derényi Imre² és Szöllősi Gergely³

^1,2,3 ELTE-MTA „Lendület” Evolúciós Genomika kutatócsoport

Self-renewing tissues of multicellular organisms produce cells using hierarhical differentaion. Such hierarhically organised tissues surpress somatic evolution and thus delay aging and the emergence of tumours at two levels of the evolutaionry process. At the level of selection, even mutations that provide a proliferative advantage can be "washed out" as a result of differntiaion [2], while at the level of mutation accumulation hierarhical organizagtion can limit the number of cell divisions, and as a result the mutaional burden of maintaining tissues [1].

Here we explore the structure of hierarchical tissues that minimize somatic evolution. We introduce a generic quantity, the self-renewal potential, which quantifies the ability of cells to avoid being "washed out" and determines their fitness at a hierarchical level. Using the self-renewal potential, which in healthy tissue is negative for non stem cells, the critical number of mutations, necessary for triggering neoplastic progression at a certain hierarchical level can be obtained. We are able to analytically estimate the probability of neoplastic progression in hierarhical tissues using the theory of birth death processes and the statistical characteristics of the cell-linage tree. We find that in general there is 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 cell is higher than the extremely low rates required to minimize mutation accumulation alone. 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.

Irodalom

[1] Hierarchical tissue organization as a general mechanism to limit the accumulation of somatic mutations, Imre Derenyi, Gergely J Szollosi Nature Communications volume 8, Article number: 14545 (2017) https://doi.org/10.1038/ncomms14545

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

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.

Kiss Máté
Tissue hierarchies in plants can efficiently minimize somatic evolution and act as a functional germline

Aug 29 - csütörtök

09:05 – 09:20

Elméleti biofizika

E36

Tissue hierarchies in plants can efficiently minimize somatic evolution and act as a functional germline

Kiss Máté¹, Derényi Imre¹ és Szöllősi Gergely János¹

¹ Eötvös Loránd Tudományegyetem Biológiai Fizikia Tanszék,

ELTE-MTA „Lendület” Evolúciós Genomika Kutatócsoport

Plant growth is governed by cell divisions in the apical meristems, which are tissues of undifferentiated cells in the shoot buds. The central zone of each meristem harbors a small group of slowly dividing stem cells. From time to time meristems also produce cells that give rise to leaves and a new meristem, called axillary meristem, in the axil of each leaf. These axillary meristems have the potential to turn into apical meristems and start to form new branches, but it is not a priori known which ones.

Recent studies have found surprisingly few genetic differences between distant branches of large plants which implies that plants can manage to keep the number of cell divisions along each lineage low (less than one per year), despite the large number of constantly produced stem cells of the axillary meristems and the inherently stochastic nature of the growth process.

To understand how plants can minimize somatic evolution, we developed a hierarchical meristematic tissue model and used computer simulations to find the optimal parameters that minimize the number of cell divisions along each lineage. We found that the optimal solution involves slow stem cell divisions in the apical meristems, and an exponentially increasing divisional rate of cells away from the central zone. New axillary meristems are produced from a few cells at the edges of apical meristems via cell divisions along a perfect binary tree.

While recent empirical evidence suggests a non-segregated functional germline in plants, it has been unclear how plants are able to produce the steady source of cells with low divisional numbers that are necessary to limit intergenerational mutation rates. Our results demonstrate that there exists an efficient mechanism, which renders germline segregation unnecessary, as the tissue hierarchies underlying plant growth are themselves able to minimize the accumulation of somatic mutations to sufficient extent.

Péret Jiménez Mario
The hierarchical structure of the hematopoietic system can explain chronic myeloid leukaemia progression.

Aug 28 - szerda

13:30 – 15:30

II. Poszterszekció

P41

The hierarchical structure of the hematopoietic system can explain chronic myeloid leukaemia progression.

Pérez Jiménez Mario¹, Derényi Imre² and Szöllősi Gergely³

¹ Eötvös Loránd University, Department of Biological Physics

² Department of Biological Physics, ELTE-MTA ‘Lendulet’ Biophysics Research Group

³ Department of Biological Physics, ELTE-MTA ‘Lendulet’ Evolutionary Genomics.

Chronic myeloid leukaemia (CML) is one of the most studied and well-known cancer types. It was the first known human cancer that can be initiated by a single chromosomal abnormality, this translocation is known as the BCR-ABL1 fusion gene [1]. CML progression is divided into three phases, these can be distinguished with a bone marrow biopsy or a blood smear test. These two methods provide clear criteria for each one of the stages [2].

The initial chronic phase is characterized by a long constant evolution estimated between 5 and 7 years. This initial phase is defined by an increased number of white blood cells (WBC) and the limited presence of immature blasts cells in the blood. Despite the presence of blast cells in the blood, the full spectrum of mature cells is still present. At this point, a cytogenetic analysis will conclude that BCR-ABL1 mutated cells have replaced healthy cells.

Transition to more advanced stages of the disease is characterized by an increased amount of blast cells in the blood (above 20%). Mature cells cannot be found in blood samples anymore. Tumour heterogeneity is also common in advanced phases. Resistance to treatment and unresponsive high WBC count are stereotypic of the final stage of the disease.

A model of hierarchical differentiation [3] is used to simulate the hematopoietic system in silico. We perform simulations about the dynamics of the BCR-ABL1 mutants in a two-compartment system. Terminally differentiated cells can migrate from the bone marrow to the bloodstream in healthy conditions. The chronic phase is in agreement with increased cellularity in the bone marrow and the initial leaking of progenitor cells to the bloodstream. In the simulation, new mutations increase self-renewal and stop the differentiation capacity of cells.

Our results show that CML development can be explained based on the hierarchical structure of blood formation. The model provides a mathematical picture of CML progression, while the simulations provide with a quantitative and accurate description. Our results provide insight about cancer dynamics, from the initial mutation to final irreversible cell growth.

References

[1] Provan, Drew & Gribben, John. (2018). Molecular hematology.

[2] Junia V. Melo & David J. Barnes. Nature Reviews Cancer ,7 441453 (2007).

[3] Derényi Imre & Szöllősi Gergely J. Nature Communications, 8 14545 (2017).

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

Tibély Gergely
Szubklonális szerkezet tumorokban

Aug 28 - szerda

13:30 – 15:30

II. Poszterszekció

P43

Szubklonális szerkezet tumorokban

Tibély Gergely^1,2, Szöllősi Gergely^1,2 és Derényi Imre^1,3

¹ ELTE Biológiai Fizika Tanszék

² MTA-ELTE Evolúciós Genomika kutatócsoport

³ MTA-ELTE Statisztikus és Biológiai Fizika kutatócsoport

A tumoron belüli heterogenitás a tumorsejtek osztódása során bekövetkező tökéletlen DNS másolás következtében jelenik meg, egy szomatikus evolúciós folyamathoz vezetve. Az utóbbi években megjelent kutatások alapján a szubklonális mutációk száma jóval nagyobbnak tűnik, mint ami a humán szomatikus mutáció ráta ismert becslései alapján várható, neutrális mutációkat feltételezve [1,2]. Feltételezhető, hogy a magas mutációszámot vagy egy, az irodalminál szignifikánsan magasabb mutációs ráta okozza, vagy gyakori sejthalál, amely a sejtek leszármazását sok generációval hosszabbá teszi, ezáltal minden sejt több osztódáson megy keresztül.

A bemutatott kutatás keretében eszközöket fejlesztünk különböző mutációs ráta-halálozási ráta paraméterértékekkel rendelkező generatív modellek valószínűségének becslésére. A modell a szekvenálási hibákat is képes figyelembe venni, amelyek a gyakorlatban az empirikus adatok mutáns readjeit dominálják. A teszteredmények alapján a valós paraméterértékek visszanyerhetőek, a sejthalál és a mutációs ráta hatásai szeparálhatóak.

Irodalom

[1] Williams M J, Werner B, Barnes C P, Graham T A, Sottoriva A. Identification of neutral tumor evolution across cancer types. Nat Genet 2016; 48:238-244.

[2] Martincorena I, Campbell P J. Somatic mutation in cancer and normal cells. Science 2015; 349:1483-1489.