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1. Evidence for Drop‐Like Nuclear Deformation in Sheared Endothelial Monolayers

   https://doi.org/10.1002/smll.202506536  

   Mohajeri, Mohammad; Wang, Ting‐Ching; Agarwal, Pooja; Kaur, Simran; Kumar, Ankit; Dickinson, Richard B; Jain, Abhishek; Lele, Tanmay P (February 2026, Small)

   ABSTRACT Shear stress imparted by blood flow tends to smoothen endothelial monolayers, a response classically attributed to reduced nuclear height and nuclear reorientation along flow. However, the mechanical basis remains unclear. Here, we tested predictions of the nuclear drop model—which posits that nuclear shape changes occur at constant volume and surface area—in human umbilical vein endothelial cells (HUVECs) under physiological shear stress. HUVEC nuclear morphologies varied from smooth, flat nuclei to wrinkled, tall ones. Applying shear stress reduced the frequency of tall, wrinkled nuclei, explaining the population‐level decrease in nuclear height. Lamin A/C–depleted nuclei are highly irregular and failed to recover shapes postindentation on PDMS microposts, suggesting that lamin A/C confers nuclear surface tension. Nuclear volume and surface area remained constant under shear, consistent with the drop model, and a computational model based on these constraints successfully predicted observed nuclear shapes. Neither lamin A/C nor lamin B1 depletion prevented shear‐induced YAP nuclear localization; instead, shear detached poorly spread cells, increasing spreading, focal adhesion assembly, and cytoskeletal tension in the remaining cells, thereby promoting YAP nuclear localization. These findings revise classical interpretations of flow‐induced endothelial smoothing and show that flow‐induced YAP nuclear localization results from increased cell spreading rather than nuclear deformation. 

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2. Excess surface area of the nuclear lamina enables unhindered cell migration through constrictions

   https://doi.org/10.1126/sciadv.ads6573  

   McKee, Brendan; Abolghasemzade, Samere; Wang, Ting-Ching; Harsh, Kajol; Kaur, Simran; Blanchard, Ryan; Menon, Krishna Belraj; Mohajeri, Mohammad; Dickinson, Richard B; Lele, Tanmay P (March 2025, Science Advances)

   Cell migration through narrow spaces is essential in wound healing and metastatic spread of cancer. Cells must deform the large nucleus to fit through constricting channels. To understand the role of the nuclear lamina in limiting cell migration through constrictions, we imaged it in cells migrating through periodic constricting channels in a microdevice. The lamina underwent cycles of wrinkling and smoothing as the nucleus changed from an irregular, rounded shape in the wide channel regions between constrictions to a smooth, hourglass shape as the nucleus passed through the center of a constriction. The laminar surface area of nuclei within constrictions was measured to be at or above the computationally predicted threshold area for the nuclear volume. The channels excluded control nuclei that had insufficient excess surface area, but not nuclei lacking lamin A/C. Thus, the excess surface area of the nuclear lamina enables cell migration through constricting channels. 

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3. Transcription inhibition suppresses nuclear blebbing and rupture independently of nuclear rigidity

   https://doi.org/10.1242/jcs.261547  

   Berg, Isabel K; Currey, Marilena L; Gupta, Sarthak; Berrada, Yasmin; Nguyen, Bao V; Pho, Mai; Patteson, Alison E; Schwarz, J M; Banigan, Edward J; Stephens, Andrew D (October 2023, Journal of Cell Science)

   ABSTRACT Chromatin plays an essential role in the nuclear mechanical response and determining nuclear shape, which maintain nuclear compartmentalization and function. However, major genomic functions, such as transcription activity, might also impact cell nuclear shape via blebbing and rupture through their effects on chromatin structure and dynamics. To test this idea, we inhibited transcription with several RNA polymerase II inhibitors in wild-type cells and perturbed cells that presented increased nuclear blebbing. Transcription inhibition suppressed nuclear blebbing for several cell types, nuclear perturbations and transcription inhibitors. Furthermore, transcription inhibition suppressed nuclear bleb formation, bleb stabilization and bleb-based nuclear ruptures. Interestingly, transcription inhibition did not alter the histone H3 lysine 9 (H3K9) modification state, nuclear rigidity, and actin compression and contraction, which typically control nuclear blebbing. Polymer simulations suggested that RNA polymerase II motor activity within chromatin could drive chromatin motions that deform the nuclear periphery. Our data provide evidence that transcription inhibition suppresses nuclear blebbing and rupture, in a manner separate and distinct from chromatin rigidity. 

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4. Mechanosensitive nuclear uptake of chemotherapy

   https://doi.org/10.1126/sciadv.adr5947  

   Scott, Nicholas R; Kang, Sowon; Parekh, Sapun H (December 2024, Science Advances)

   The nucleus is at the nexus of mechanotransduction and the final barrier for most first line chemotherapeutics. Here, we study the intersection between nuclear-cytoskeletal coupling and chemotherapy nuclear internalization. We find that chronic and acute modulation of intracellular filaments changes nuclear influx of doxorubicin (DOX). Rapid changes in cell strain by disruption of cytoskeletal and nuclear filaments sensitize nuclei to DOX, whereas chronic reduction of cell strain desensitize nuclei to DOX. Extracted nuclei from invasive cancer cells lines from different tissues have distinct nuclear permeability to DOX. Last, we show that mechano-priming of cells by paclitaxel markedly improves DOX nuclear internalization, rationalizing the observed drug synergies. Our findings reveal that nuclear uptake is a critical, previously unquantified aspect of drug resistance. With nuclear permeability to chemotherapy being tunable via modulation of nuclear mechanotransduction, mechano-priming may be useful to help overcome drug resistance in the future. 

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5. Nanoscale Curvature Regulates YAP/TAZ Nuclear Localization Through Nuclear Deformation and Rupture

   https://doi.org/10.1002/advs.202415029  

   Francis, Emmet A; Sarikhani, Einollah; Patel, Vrund; Meganathan, Dhivya Pushpa; Sadr, Leah; Tahir, Anum; Jahed, Zeinab; Rangamani, Padmini (July 2025, Advanced Science)

   Abstract Nuclear translocation of the transcription regulatory proteins yes‐associated protein (YAP) and transcriptional coactivator with PDZ‐binding motif (TAZ) is a critical readout of cellular mechanotransduction. Recent experiments have demonstrated that cells on substrates with well‐defined nanotopographies demonstrate mechanoadaptation through a multitude of effects ‐ increased integrin endocytosis as a function of nanopillar curvature, increased local actin assembly on nanopillars but decreased global cytoskeletal stiffness, and enhanced nuclear deformation. How do cells respond to local nanotopographical cues and integrate their responses across multiple length scales? This question is addressed using a biophysical model that incorporates plasma membrane (PM) curvature‐dependent endocytosis, PM curvature‐sensitive actin assembly, and stretch‐induced opening of nuclear pore complexes (NPCs) in the nuclear envelope (NE). This model recapitulates lower levels of global cytoskeletal assembly on nanopillar substrates, which can be partially compensated for by local actin assembly and NE indentation, leading to enhanced YAP/TAZ transport through stretched NPCs. Using cell shapes informed by electron micrographs and fluorescence images, the model predicts lamin A and F‐actin localization around nanopillars, in agreement with experimental measurements. Finally, simulations predict nuclear accumulation of YAP/TAZ following rupture of the NE and this is validated by experiments. Overall, this study indicates that nanotopography tunes mechanoadaptation through both positive and negative feedback on mechanotransduction. 

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