Design by Ivana Šarić
ERC Synergy Grant
Molecular origins of aneuploidies in healthy and diseased human tissues — ANEUPLOIDY
Chromosome segregation errors cause aneuploidy, a state of karyotype imbalance that accelerates tumor formation and impairs embryonic development. Even though mitotic errors have been studied extensively in cell cultures, the mechanisms generating various errors, their propagation and effects on genome integrity are not well understood. Moreover, very little is known about mitotic errors in complex tissues. The main goal of this project is to uncover the molecular origins of mitotic errors and their contribution to karyotype aberrations in healthy and diseased tissues. To achieve our goal, we have assembled an interdisciplinary team of experts in molecular and cell biology, cell biophysics, chromosomal instability in cancer, and theoretical physics. Our team will introduce novel approaches to study aneuploidy (superresolution microscopy, optogenetics, laser ablation, single cell karyotype sequencing) and apply them to state-of-the-art tissue cultures (mammalian organoids and tumoroids). In close collaboration, Tolić will establish assays to detect and quantify error types in cells, and Kops and Amon will use the assays on various healthy and cancer tissues. Tolić and Kops will uncover the molecular origins of errors, their propagation and impact on genome integrity, while Amon will lead the investigation of the mechanisms that ensure high chromosome segregation fidelity in healthy tissues. Interwoven in these collaborations are the efforts of Pavin, who will develop a theoretical model to describe the origin of errors and to quantitatively link chromosome segregation fidelity in single cells and tissues. Model and experiment will continuously inspire each other, to achieve deep understanding of how mitotic errors arise, how they propagate and how they impact on cell populations. Thus, the extensive sets of expertise present in our team will be combined and expanded with novel technologies to tackle the big challenge of the origins of aneuploidy in humans.
Researchers (PIs): Iva Tolić, Geert Kops, †Angelika Amon, Nenad Pavin
Host Institutions (HIs): Ruđer Bošković Institute, Royal Netherlands Academy of Arts And Sciences, Massachusetts Institute of Technology (MIT), University of Zagreb - Faculty of Science
Countries: Croatia, Usa, Netherlands
Call Details: Synergy Grants (SyG), ERC-2019-SyG
GA number: 855158
ERC funding: 10 million € for six years
Duration: Start date: April 1, 2020, End date: March 31, 2026
P. Risteski, D. Božan, M. Jagrić, A. Bosilj, N. Pavin and I.M. Tolić
Length-dependent poleward flux of sister kinetochore fibers promotes chromosome alignment.
Cell Reports 40, 111169 (2022). [View PDF]
A. Ivec, M. Trupinić, I.M. Tolić and N. Pavin
Oblique circle method for measuring the curvature and twist of mitotic spindle microtubule bundles.
Biophys J (2021) https://doi.org/10.1016/j.bpj.2021.07.024. [View PDF]
P. Risteski, M. Jagrić, N. Pavin and I.M. Tolić
Biomechanics of chromosome alignment at the spindle midplane.
Curr Biol 31, R574-R585 (2021).
I.M. Tolić and N. Pavin
Mitotic spindle: Lessons from theoretical modeling.
Mol Biol Cell 32, 218–222 (2021). [View PDF]
N. Pavin and I.M. Tolić
Mechanobiology of the Mitotic Spindle.
Dev Cell 56, 192-201 (2021). [View PDF]
26. 08. 2021.
Meeting of the ERC project Molecular origins of aneuploidies in healthy and diseased human tissues (Aneuploidy), was held in Dubrovnik at Hotel Kompas, from 25-29 August 2021. After two larger meetings held online, this is the first project meeting organized in person.
Even though mitotic errors have been studied extensively in cell cultures, the mechanisms generating various errors, their propagation and effects on genome integrity are not well understood. Moreover, very little is known about mitotic errors in complex tissues. This project, which aims to uncover the molecular origins of mitotic errors and their contribution to karyotype aberrations in healthy and diseased tissues, started in April 2020 and will last for six years.
Principal investigators on the project are Iva Tolić from the Ruđer Bošković Institute, Geert Kops from the Hubrecht Institute – KNAW, team of researchers from the Massachusetts Institute of Technology and Nenad Pavin from the Faculty of Science, University of Zagreb.
The meeting gathered 15 researchers who presented latest research results in mechanisms of the oncogenic properties of chromosomal instability, behaviour of polar chromosomes during late – alingment in diploid human cells, PRC1 – labelled bundle formation during spindle development, aneuploidy in mouse small intestine organoids, photoconversion as a tool to study chromosome segregation, and development of physical and mathematical models that explain gain and chromosome alignment.
Aside from talks held by the project team members, researchers were grouped in several discussion groups to find constructive solutions to the specific questions encountered in the research so far. Discussion groups touched on topics such as recurrent aneuploidy patterns in cancer, possible causal links between chromosome instability and epithelial – mesenchymal transition, the role of chromosome instability in tumor cell development, the influence of errors during mitosis on cell population and the formation of further experiments and theoretical foundations.
This meeting enabled synergy of different scientific areas and discovery of solutions and directions in the following experimental and theoretical work.
The project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement Nº855158 in the scope of the European Research Council Synergy program.
17. 02. 2021.
Zoom meeting of ERC Synergy project Molecular origins of aneuploidies in healthy and diseased human tissues (Aneuploidy) had taken place on Wednesday, February 17th 2021. International team members had discussed their current progress and future directions.
Five participants from international teams presented their work on the project goals. MIT team gave a presentation about consequences of chromosome missegregation in physiology and disease. Kops team gave presentation on tolerating mistakes to answer how cancer cells cope with CIN and a particular case of human aneuploidy. Tolić team presented work on bridging microtubules and beyond and the mechanism of overlap length-dependent chromosome alignment.
Every presentation was followed by a discussion in a form of questions and answers. This meeting was a great opportunity for different team members to identify the current progress of the project goals and to discuss difficulties and finding discovered during their work. New possible directions of work were pointed out.