Hyperwrinkling of the nuclear lamina is associated with attenuated mechanosensitivity in giant nucleated cancer cells

Polyploid giant cancer cells (PGCCs) are chemoresistant tumor cells associated with poor patient outcomes. PGCCs in tissue are identified by their extremely large sizes and the presence of massive or several nuclei. Although nuclear dysmorphia is also a common characteristic of tumor cells, little is known about the shape of nuclei in PGCCs. We show that the nuclear lamina in giant nucleated PGCCs is highly wrinkled across diverse cancer patient tissues. We investigated the cause of this hyperwrinkling in ovarian PGCCs in vitro. Laminar hyperwrinkling in PGCCs was independent of cell shape or cytoskeletal forces. Instead, measurements combined with computational modeling show that laminar hyperwrinkling is an intrinsic property of PGCCs, arising from a disproportionate amount of laminar excess area. PGCCs also displayed attenuated mechanosensitivity of cell spreading and YAP nuclear localization compared with control cells. Thus, laminar hyperwrinkling may disrupt PGCC mechanobiological pathways, slowing their proliferation.