Deciphering the molecular mechanism of the cancer formation by chromosome structural dynamics

Cancer reflects the dysregulation of the underlying gene network, which is intimately related to the 3D genome organization. Numerous efforts have been spent on experimental characterizations of the structural alterations in cancer genomes. However, there is still a lack of genomic structural-level understanding of the temporal dynamics for cancer initiation and progression. Here, we use a landscape-switching model to investigate the chromosomal structural transition during the can-cerization and reversion processes. We find that the chromosome undergoes a non-monotonic structural shape-changing pathway with initial expansion followed by compaction during both of these processes. Furthermore, our analysis reveals that the chromosome with a more expanded structure than those at both the normal and cancer cell during cancerization exhibits a sparse contact pattern, which shows significant structural similarity to the one at the embryonic stem cell in many aspects, including the trend of contact probability declining with the genomic distance, the global structural shape geometry and the spatial distribution of loci on chromosome. We show that cell cancerization and reversion are highly irreversible processes in terms of the chromosomal structural transition pathways, spatial repositioning of chromosomal loci and hysteresis loop of contact evolution analysis. Our model draws a molecular-scale picture of cell cancerization, which contains initial reprogramming towards the stem cell followed by differentiation towards the cancer cell, accompanied by an initial increase and subsequent decrease of cell stemness.