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The three-dimensional (3D) architecture of the genome is emerging as a novel target for anti-cancer therapy. The overarching goal of this project is to deepen our knowledge on forces that shape the 3D genome, in order to build a predictive model of genome architecture. In turn, this model can be used to reconstruct the 3D genome of cancer cells and expose potential vulnerabilities hidden in the higher-order structure of their abnormal genomes. We do this by pursuing four complementary aims. In Aim 1, we leverage on our GPSeq method (Girelli et al., Nat Biotech 2020) to expose the blueprint of the 3D genome which we believe is already present in mitotic chromosomes. In Aim 2, we build on our preliminary observations in order to identify novel factors that shape the 3D genome as well as cancer-specific 3D genome rearrangements. In Aim 3, we use chemical and genetic perturbations to rewire the karyotype and then assess how this changes the 3D genome and gene expression. Finally, in Aim 4, we build on our modelling expertise and data generated in Aim1-3 to build a model to predict how the 3D genome gets reshaped in cancer cells and to identify cancer-specific 3D genome vulnerabilities that can serve as new therapeutic target. This is an ambitious research program that aims at tackling fundamental unresolved questions in the field of genome organization and uncovering the pathogenic role of 3D genome alterations in cancer, potentially paving the way to novel treatment strategies.