FROM MICRONUCLEI TO EMT: MOLECULAR MECHANISMS OF GENOMIC INSTABILITY AND CELLULAR PLASTICITY

Chromosomal instability and its cellular consequences represent critical aspects of cancer progression and genomic instability. The research presented in this thesis encompasses two complementary projects, focusing on distinct yet interconnected molecular pathways. The first project investigates the role of the autophagic receptor p62 in regulating micronuclear integrity. Utilizing advanced methodologies, including proximity labeling and mass spectrometry, this study reveals how p62 recognizes micronuclei through ubiquitination and proximity to mitochondria, with ROS-induced homo-oligomerization of p62 driving micronuclear envelope rupture. These findings uncover a critical mechanism by which p62 modulates nuclear membrane stability, influencing chromosomal rearrangements and genomic instability through its interaction with ESCRT components. The second project explores the impact of chromosomal mis-segregation on cellular behavior, specifically its role in inducing Epithelial-to-Mesenchymal Transition, a pivotal process in cancer metastasis. By employing transcriptomic analysis, cellular migration assays, and intercellular signaling studies, my work demonstrates how aneuploidy influences cellular plasticity and activates key pathways such as NF-κB and TGF-β. Notably, this study emphasizes the influence of aneuploid cells on the plasticity of neighboring cells and also highlight the importance of late-stage events often overlooked in genomic instability research. Together, these projects elucidate the intricate molecular relationships between chromosomal instability, autophagic pathways, and EMT, providing insights into the mechanisms that drive tumorigenesis and metastasis.