(447c) Abnormal Nuclear Morphologies in Cancer: Role of Chromatin Regulators

While the nucleus of a normal, healthy cell has a smooth and uniform ellipsoidal shape, the nucleus of a cancer cell commonly has irregularities in its contour including invaginations, folds, and lobes. These nuclear irregularities are prognostic and diagnostic markers of cancer, but the mechanisms by which these nuclear irregularities manifest in cancer remain poorly understood. Recent research efforts have focused on cytoskeletal forces onto the mechanically ‘soft’ cancer nucleus as potential causes of abnormal shapes. However, intranuclear forces, such as those generated from chromatin remodeling, may also be important but have received less attention.

Here we screened a library of chromatin regulators to discover proteins that are required for maintenance of normal nuclear shapes. Nuclear shapes were quantified using an elliptical Fourier analysis and top candidates were selected for further mechanistic studies. Features in the nuclear lamina (such as holes, grooves, and folds) were identified by an automated texture analysis. A library of epigenetic pharmacological agents was also screened and common agents that affect nuclear shape and lamin structure, in both model breast epithelial cells and metastatic breast cancer, were identified. Our results identify key epigenetic genes that may be involved regulating nuclear morphology.