Epithelial-Mesenchymal Plasticity is regulated by inflammatory signalling networks coupled to cell morphology

Abstract

The shape, size, and architecture of the nucleus determines the output of transcriptional programmes. As such, the ability of the nucleus to resist deformation and maintain its shape is essential for homeostasis. Conversely, changes in nuclear shape can alter transcription and cell state. The ability of cells to deform their nuclei is also essential for cells to invade confined spaces. But how cells set the extent of nuclear deformability in response to their environment is unclear. Here we show that the cell-cell adhesion protein JAM3 regulates nuclear shape. In epithelial cells, JAM3 is required for maintenance of nuclear shape by organizing microtubule polymers and promoting LMNA stabilization in the nuclear membrane. Depletion of JAM3 in normal epithelial cells leads to dysmorphic nuclei, which leads to differentiation into a mesenchymal-like state. Inhibiting the actions of kinesins in JAM3 depleted cells restores nuclear morphology and prevents differentiation into the mesenchymal-like state. Critically, JAM3 expression is predictive of disease progression. Thus JAM3 is a molecule which allows cells to control cell fates in response to the presence of neighbouring cells by tuning the extent of nuclear deformability. 3 IntroductionNuclear shape, size and architecture define the biophysics of key cellular processes such as transcription, replication, mRNA export, and DNA damage repair 1-4 . But nuclei are malleable viscoelastic structures 5, 6 that are frequently being stretched, strained, and compressed both by extracellular forces 7 , and the internal cytoskeleton 8-12 . Mechanisms have evolved to maintain nuclear shape and genome organization when cells are exposed to these forces 13 .Indeed, dysregulation of nuclear shape is coincident with numerous diseases including: muscular dystrophies, heart disease, and aging disorders such as progeria [14][15][16][17][18] . Thus in many cells, maintaining nuclear shape is essential for homeostasis.But while clearly maintenance of nuclear shape, size, and genome organization is essential for cellular homeostasis, transcriptional programmes that alter cell fate can be engaged by altering nuclear morphology and architecture 1,5,[19][20][21][22] . For example, nuclei undergo extensive shape changes that drive differentiation during development 23 . One means by which alteration in nuclear shape affects transcription is by affecting the nuclear translocation dynamics of transcription factors such as YAP/TAZ and NF-κB 24, 25 . Thus while in some cell types nuclear shape and genome organization are robust to deformation, in other cell types the nucleus is highly deformable.The importance of maintaining nuclear shape for cell, tissue, and organism homeostasis is highlighted by the fact that changes in nuclear morphology and genome organization are associated with cancer 4, 26 . For example, nuclear rupture is frequently an oncogenic event 27,28 . Indeed, pathologists have used nuclear shape as a diagnostic for over a century 29 . Irregular nuclear shapes and sizes are hall...

Defined Microenvironments Trigger In Vitro Gastrulation in Human Pluripotent Stem Cells

“…During this time course we also measured changes in nuclear geometry, where variations in morphology has been demonstrated during EMT, differentiation and de‐differentiation. [ 40 , 41 ] Cells confined on 10 kPa hydrogels produce more elongated nuclei with increased nuclear perimeter and decreased circularity over time compared to cells confined on glass (Figure 3D,E ). We also performed a zonal analysis to evaluate nuclear changes between the border and interior of the patterns.…”

Boolean modeling of mechanosensitive epithelial to mesenchymal transition and its reversal

“…These include the stiffness-dependent effects of TGF-β, leading to apoptosis on soft ECM versus EMT on stiff substrates, 46 the demonstration of full EMT in the absence of any biochemical transforming signal on stiff nano-patterned ECMs, 47 mechanical stress-mediated EMT transcription factor induction, 48 , 49 , 50 or the effect of cytoskeletal and nuclear morphology on the transcriptional regulation of EMT. 51 Yet, we lack predictive mechanistic model that can reproduce and predict the effects of a single cell’s biomechanical environment on its behavior in different signaling contexts, such as varying growth stimuli or transforming signals. Moreover, current computational models only address the process of MET in response to either the withdrawal of input signals that activate Snai1 , 26 , 27 , 30 or to drugs/mutations.…”

Epithelial‐to‐mesenchymal transition as a learning paradigm of cell biology

“…During EMT there is a repositioning of the nucleus, which moves to the posterior end of migrating cells. Disruption of normal cell‐cell adhesion causes changes in microtubule organization that can in turn deform nuclei and upregulate the activity of pro‐EMT transcription factors (Garcia et al, 2022). Furthermore, recent data reveal that EMT alters the organization of nuclear domains and the spatiotemporal organization of the genome.…”