The tubule-sheet continuum model links the pattern of nuclear envelope assembly to nuclear envelope integrity

Nuclear envelope (NE) fragility is associated with a variety of human diseases. However, major questions about the causes of NE fragility are unresolved. In particular, the relationship between NE fragility and NE assembly is unclear. Here, using a panel of 13 mammalian cell lines, we show that normal cells and some cancer cells assemble the NE using distinct patterns from opposite ends of the "tubule-sheet continuum", and that the NE assembly pattern more utilised in cancer cells is a source of NE fragility. In normal cells, the mitotic endoplasmic reticulum (ER) morphology is dominated by ER tubules or small sheets and the NE assembles by "membrane infiltration". By contrast, in some cancer cells, the mitotic ER morphology is dominated by large ER sheets and the NE assembles by "lateral sheet expansion". Experimental manipulations that promote mitotic ER sheet formation and NE assembly by lateral sheet expansion in normal cells result in NE fragility. Thus, we propose that NE assembly by lateral sheet expansion is a source of NE fragility in cancer cells.