The main aim of this thesis of Ruifang Tian is to investigate how CIN influences tumor behavior through intrinsic signalling, extracellular communication, and immune regulation, and to explore how these pathways may be leveraged for therapeutic targeting. This thesis describes several CIN-induced stress responses and adaptive mechanisms. We examine how CINhigh triple-negative breast cancer (TNBC) cells regulate the recruitment and polarization of M1/M2 tumor macrophages; how acute CIN in TNBC cells enhances extracellular-vesicle (EV) secretion and promotes cell migration through EFEMP1-dependent signaling; and how p21high cell states, characterized through multi-omics analyses, promote CIN tolerance by releasing EVs that remodel the microenvironment. Furthermore, a CRISPR-based functional screen identifies CDC20 as a key determinant of sensitivity to spindle-checkpoint inhibition, with its high expression in aneuploid cells revealing a potential vulnerability.
Together, this work provides new insights into the multifaceted consequences of CIN and outlines several promising avenues for selectively targeting CIN-high tumors in the future.
