Fibrosis compromises pancreatic ductal carcinoma (PDAC) treatment and contributes to patient mortality yet anti-stromal therapies are controversial. We found that human PDACs with impaired epithelial transforming growth factor β (TGF-β) signaling have elevated epithelial Stat3 activity and develop a stiffer, matricellular-enriched fibrosis associated with high epithelial tension and shorter patient survival. In several Kras-driven mouse models, both the loss of TGF-β signaling and elevated β1-integrin mechanosignaling engaged a positive feedback loop whereby Stat3 signaling promotes tumor progression by increasing matricellular fibrosis and tissue tension. In contrast, epithelial Stat3 ablation attenuated tumor progression by reducing the stromal stiffening and epithelial contractility induced by loss of TGF-β signaling. In PDAC patient biopsies, higher matricellular protein and activated Stat3 associated with SMAD4 mutation and shorter survival. The findings implicate epithelial tension and matricellular fibrosis in the aggressiveness of SMAD4 mutant pancreatic tumors, and highlight Stat3 and mechanics as key drivers of this phenotype.

Highlights d Stretch triggers amplitude-dependent supracellular and nuclear mechanoresponses d H3K9me3 heterochromatin mediates nuclear stiffness and membrane tension d Nuclear deformation-triggered Ca 2+ alters chromatin rheology to prevent DNA damage d Supracellular alignment redistributes stress to restore chromatin state

Increased overall survival for patients with glioma brain tumours is associated with mutations in the metabolic regulator isocitrate dehydrogenase 1 (IDH1). Gliomas develop within a mechanically challenged microenvironment that is characterized by a dense extracellular matrix (ECM) that compromises vascular integrity to induce hypoxia and activate HIF1α. We found that glioma aggression and patient prognosis correlate with HIF1α levels and the stiffness of a tenascin C (TNC)-enriched ECM. Gain- and loss-of-function xenograft manipulations demonstrated that a mutant IDH1 restricts glioma aggression by reducing HIF1α-dependent TNC expression to decrease ECM stiffness and mechanosignalling. Recurrent IDH1-mutant patient gliomas had a stiffer TNC-enriched ECM that our studies attributed to reduced miR-203 suppression of HIF1α and TNC mediated via a tension-dependent positive feedback loop. Thus, our work suggests that elevated ECM stiffness can independently foster glioblastoma aggression and contribute to glioblastoma recurrence via bypassing the protective activity of IDH1 mutational status.

To establish and maintain organ structure and function, tissues need to balance stem cell proliferation and differentiation rates and coordinate cell fate with position. By quantifying and modelling tissue stress and deformation in the mammalian epidermis, we find that this balance is coordinated through local mechanical forces generated by cell division and delamination. Proliferation within the basal stem/progenitor layer, which displays features of a jammed, solid-like state, leads to crowding, thereby locally distorting cell shape and stress distribution. The resulting decrease in cortical tension and increased cell-cell adhesion trigger differentiation and subsequent delamination, reinstating basal cell layer density. After delamination, cells establish a high-tension state as they increase myosin II activity and convert to E-cadherin-dominated adhesion, thereby reinforcing the boundary between basal and suprabasal layers. Our results uncover how biomechanical signalling integrates single-cell behaviours to couple proliferation, cell fate and positioning to generate a multilayered tissue.

Cells are constantly subjected to a spectrum of mechanical cues, such as shear stress, compression, differential tissue rigidity and strain, to which they adapt by engaging mechanisms of mechanotransduction. While the central role of cell adhesion receptors in this process is established, it has only recently been appreciated that mechanical cues reach far beyond the plasma membrane and the cytoskeleton, and are directly transmitted to the nucleus. Furthermore, changes in the mechanical properties of the perinuclear cytoskeleton, nuclear lamina and chromatin are critical for cellular responses and adaptation to external mechanical cues. In that respect, dynamic changes in the nuclear lamina and the surrounding cytoskeleton modify mechanical properties of the nucleus, thereby protecting genetic material from damage. The importance of this mechanism is highlighted by debilitating genetic diseases, termed laminopathies, that result from impaired mechanoresistance of the nuclear lamina. What has been less evident, and represents one of the exciting emerging concepts, is that chromatin itself is an active rheological element of the nucleus, which undergoes dynamic changes upon application of force, thereby facilitating cellular adaption to differential force environments. This Review aims to highlight these emerging concepts by discussing the latest literature in this area and by proposing an integrative model of cytoskeletal and chromatin-mediated responses to mechanical stress.