Nenad Pavin Group

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

Publications

I. Sigmund, D. Božan, I. Šarić, and N. Pavin
Mechanisms of Chromosome Positioning During Mitosis
PRX Life [View PDF]
https://doi.org/10.1103/PRXLife.2.043017