A close collaboration between our four Synergy groups resulted in 9 joint publications between at least two groups, covering several exciting findings. Using the expertise of the Kops lab in single-cell DNA sequencing and organoids, we have shown that chromosomes have different segregation error frequencies that correlate with their location in the interphase nucleus, and in combination with the expertise of the Tolić lab in high-end imaging, we have found a "danger zone" for chromosomes behind spindle poles (Klaasen et al., Nature 2022). Collaboration between the Kops and Tolić labs continued with the finding that centromere chromatin is organized into a two-domain structure in mitosis, with lagging chromosomes in cancer cells having the two subdomains bound to opposite spindle poles (Sacristan et al., Cell 2024). This teamwork is currently extended to explore the chromosome instability in patient-derived organoids and organoids from a genetically engineered mouse model for chromosomal instability (CiMKi), generated by the Kops lab. Development of a mathematical model based on a novel concept of macro-karyotype by the Pavin group, in collaboration with MIT and the Tolić lab, has shown that tumor karyotypes can be explained by proliferation-driven evolution of aneuploid cells (Ban et al., Biophys J 2023). This theoretical approach has been extended to describe karyotype evolution in organoids during tumor development, in a collaboration between the Pavin and Kops groups. A teamwork between the Tolić and Pavin groups revealed that poleward flux of kinetochore fibers promotes chromosome alignment (Risteski et al., Cell Rep 2022). In this work the Tolić lab developed speckle microscopy in human spindles and showed that kinetochore fiber flux is length-dependent, and the Pavin group introduced a flux-driven centering model that provides a physical explanation for chromosome alignment. This collaboration further showed that the formation of the mitotic spindle relies on a network-to-bundles transition of microtubules driven by kinetochores and chromosomes (Matković et al., Nat Commun 2022). Continuing studies on the chirality of the mitotic spindle, the Pavin and Tolić groups developed a novel method to quantify spindle shape (Ivec et al., Biophys J 2021). In total, we published 16 original papers in top journals such as Nature, Curr Biol, J Cell Biol, eLife, and 7 reviews. The Synergy team is now exploring the mechanisms of chromosome congression and how the spindle adapts to polyploidy, including the formation of multipolar spindles.
