Aberrations in nuclear size and shape are commonly used to identify cancerous tissue. However, it remains unclear whether the disturbed nuclear structure directly contributes to the cancer pathology or is merely a consequence of other events occurring during tumorigenesis. Here, we show that highly invasive and proliferative breast cancer cells frequently exhibit Akt-driven lower expression of the nuclear envelope proteins lamin A/C, leading to increased nuclear deformability that permits enhanced cell migration through confined environments that mimic interstitial spaces encountered during metastasis. Importantly, increasing

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The vertebrate intestine forms by asymmetric gut rotation and elongation, and errors cause lethal obstructions in human infants. Rotation begins with tissue deformation of the dorsal mesentery, which is dependent on left-sided expression of the Paired-like transcription factor Pitx2 . The conserved morphogen Nodal induces asymmetric Pitx2 to govern embryonic laterality, but organ-level regulation of Pitx2 during gut asymmetry remains unknown. We found Nodal to be dispensable for Pitx2 expression during mesentery deformation. Intestinal rotation instead required a mechanosensitive latent transforming growth factor–β (TGFβ), tuning a second wave of Pitx2 that induced reciprocal tissue stiffness in the left mesentery as mechanical feedback with the right side. This signaling regulator, an accelerator (right) and brake (left), combines biochemical and biomechanical inputs to break gut morphological symmetry and direct intestinal rotation.

Nuclei within cells are constantly subjected to compressive, tensile and shear forces, which regulate nucleoskeletal and cytoskeletal remodeling, activate signaling pathways and direct cell-fate decisions. Multiple rheological methods have been adapted for characterizing the response to applied forces of isolated nuclei and nuclei within intact cells. However, in vitro measurements fail to capture the viscoelastic modulation of nuclear stress-strain relationships by the physiological tethering to the surrounding cytoskeleton, extracellular matrix and cells, and tissue-level architectures. Using an equiaxial stretching apparatus, we applied a step stress and measured nucleus deformation dynamics within living C. elegans nematodes. Nuclei deformed non-monotonically under constant load. Non-monotonic deformation was conserved across tissues and robust to nucleoskeletal and cytoskeletal perturbations, but it required intact Linker of Nucleoskeleton and Cytoskeleton (LINC) complex attachments. The transition from creep to strain recovery fits a tensile-compressive linear viscoelastic model that is indicative of nucleoskeletal-cytoskeletal decoupling under high load. Ce-lamin ( lmn-1) knockdown softened the nucleus whereas nematode ageing stiffened the nucleus and decreased deformation recovery rate. Recovery lasted minutes rather than seconds due to physiological damping of the released mechanical energy thus protecting nuclear integrity and preventing chromatin damage.

Aberrations in nuclear size and shape are commonly used to identify cancerous tissue. However, it remains unclear whether the disturbed nuclear structure directly contributes to the cancer pathology or is merely a consequence of other events occurring during tumorigenesis. Here, we show that highly invasive and proliferative breast cancer cells have lower expression of the nuclear envelope proteins lamin A/C, leading to increased nuclear deformability that permits enhanced cell migration through confined environments that mimic interstitial spaces encountered during metastasis. Importantly, increasing lamin A/C expression in highly invasive breast cancer cells altered expression of numerous other proteins implicated in metastatic progression. Further supporting an important role of lamins in breast cancer metastasis, analysis of lamin levels in human breast tumors revealed a significant association between lower lamin A levels and decreased disease-free survival. These findings suggest that downregulation of lamin A/C may influence both biochemical and physical properties of the cell to promote breast cancer metastatic progression.