To spread from a localized tumor, metastatic cancer cells must squeeze through constrictions that cause major nuclear deformations. Since chromosome structure affects nucleus stiffness, gene regulation, and DNA repair, here, we investigate the relationship between 3D genome structure and constricted migration in cancer cells. Using melanoma (A375) cells, we identify phenotypic differences in cells that have undergone multiple rounds of constricted migration. These cells display a stably higher migration efficiency, elongated morphology, and differences in the distribution of Lamin A/C and heterochromatin. Hi‐C experiments reveal differences in chromosome spatial compartmentalization specific to cells that have passed through constrictions and related alterations in expression of genes associated with migration and metastasis. Certain features of the 3D genome structure changes, such as a loss of B compartment interaction strength, are consistently observed after constricted migration in clonal populations of A375 cells and in MDA‐MB‐231 breast cancer cells. Our observations suggest that consistent types of chromosome structure changes are induced or selected by passage through constrictions and that these may epigenetically encode stable differences in gene expression and cellular migration phenotype.

To spread from a localized tumor, metastatic cancer cells must squeeze through constrictions that cause major nuclear deformations. Since chromosome structure affects nucleus stiffness, gene regulation and DNA repair, here we investigate how confined migration affects or is affected by 3D genome structure. Using melanoma (A375) cells, we identify phenotypic differences in cells that have undergone 10 rounds of constricted migration. These cells display a stable increase in migration efficiency, elongated morphology, and an abnormal distribution of Lamin A/C and heterochromatin. Using Hi-C, we observe changes in chromosome spatial compartmentalization specific to constricted cells and related alterations in expression of genes associated with migration and metastasis. These cells also show increased nuclear deformations when cultured in a 3D collagen matrix and altered behavior when co-cultured with fibroblasts in organoids. Our observations reveal a relationship between chromosome structure changes, metastatic gene signatures, and the abnormal nuclear appearance of aggressive melanoma.

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