Dividing human cells face two key competing tasks: faithfully segregating sister chromatids while avoiding long mitotic delays. The mitotic spindle rapidly attaches and aligns most chromosomes on the metaphase plate, but polar chromosomes, which start behind the emerging spindle poles, offer a particular challenge. Recent work in the Tolić laboratory showed that polar chromosomes are especially prone to being mis-segregated in cancer cells. How polar chromosomes are formed and resolved is, however, poorly understood. Interestingly, the two spindle poles are not equal in their ability to deal with polar chromosomes, as work of the Meraldi laboratory has established that the pole containing the old centrosome accumulates more polar chromosomes. Thus, the central hypothesis of this project is that centrosome age affects the formation, resolution, and fate of polar chromosomes. The main goal of this collaborative effort is to decipher the molecular and biophysical mechanisms controlling polar chromosomes, by combining the expertise of the Meraldi laboratory in centrosome age-dependent asymmetries and the Tolić laboratory in the biomechanics of polar chromosomes. We will investigate and manipulate the spindle parameters affecting polar chromosomes in human cell lines with a large spectrum of polar chromosomes asymmetries, and in a physiological context of Drosophila neuroblasts. This project will synergistically benefit from the expertise developed in both laboratories, including cutting-edge live-cell imaging assays, super-resolution microscopy, laser ablation, as well as theoretical modelling in collaboration with Nenad Pavin. Overall, the project will reveal a mechanistic link between the initial location of the chromosomes with respect to the old and young centrosome with the accuracy of their segregation, providing understanding of the origin of a prominent cause of chromosome segregation errors in cancer cells.