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Nuclear Integrity in Health and Disease

The nuclear envelope (NE) is the double lipid bilayer that encloses the genome, ensuring nucleocytoplasmic compartmentalization and spatial organization of cellular processes, regulating signal transduction and chromatin functionalization. Rather than being a static entity, the nuclear envelope rapidly changes its shape and integrity, its composition and associated proteome in response to extracellular and intracellular cues, triggering a variety of signalling cascades. Whereas it is clear that the nuclear envelope plays critical roles in ensuring cell fitness, we are only just beginning to understand the many dynamic processes that are orchestrated by the nuclear envelope.

Main research question

The Nuclear envelope dynamics project aims to characterize the pathways triggered by changes in NE topology, and to understand how these pathways affect cell fitness and fate. To address this, we focus on

The mechanistic regulation of NE integrity during interphase and cell division
The effects of compromised of NE integrity on genome integrity, cell fitness and fate in Glioblastoma models.
The contribution of compromised NE integrity to the development of diseases such as cancer and progressive liver steatosis.
The adaptive mechanisms of intrinsic NE mechano-resilience upon exposure to mechanical strain during cancer cell invasion.

To address these questions, we use mechanistic cell biological studies that revolve around advanced live-cell microscopy, proteomics, and molecular genetics approaches in 2D and 3D non-transformed (e.g. iPSCs) and cancer cell models, as well as through in vivo mouse models.

Movie: Cells undergo transient loss of nuclear integrity, as monitored by leakage of a nuclear fluorescent marker into the cytosol (in red, mCherry-NLS). These ruptures are accompanied by transient recruitment of the membrane repair machinery to the sites of rupture (in green, CHMP4B-mNG) resulting in restoration of nuclear integrity as evidenced by nuclear re-accumulation of mCherry-NLS.