Biology subjects

Sun, S. X.

Publications and source records attributed to Sun, S. X..

10 recordsLinked to original sources

bioRxiv2026

Mechanochemical cues control the coupling of metabolic and migratory patterns in cancer

Confined migration is essential for metastasis, yet how cells adapt their migratory and metabolic programs across stiffness-varying microenvironments remains unclear. We uncover a stiffness-dependent mechano-metabolic switch governing migration. In stiff microchannels, cells utilize the osmotic engine model (OEM), relying on NHE1 activity, front-polarization, and glycolysis. In soft microchannels, migration is OEM-independent and requires pyruvate-fueled oxidative phosphorylation (OxPHOS). This OxPHOS-driven motility depends on Arp3, {beta}1-integrin and integrin-linked kinase, which increase membrane tension in confinement that in turn triggers TRPM7-mediated calcium influx and RhoA-/myosin-II contractility. Activating and polarizing NHE1, via overexpression, hypoxia or elevated viscosity, restore OEM- and glycolysis-dependent migration in soft microchannels, bypassing the need for actin polymerization in vitro and in chick embryos. Mitochondria addition reinstates Arp3 polarization and enhances migration in NHE1-overexpressing cells, enabling engagement of both mechanisms in vitro and in zebrafish. These findings uncover a previously unrecognized mechano-metabolic link, revealing that intracellular rewiring overrides stiffness-dependent metabolic demands.

cell biology↗

bioRxiv2026

Whole organism 3D mapping reveals universal branching topology and biophysical optimization governs vascular and nervous system development

The vascular and nervous systems are transport networks essential for life, yet whether universal geometric and topological principles govern their formation remains unclear. The organism-wide molecular and biophysical coordination required to build and maintain these networks during embryonic development has inspired decades of theoretical work, offering predictions about their expected organization. However, the lack of complete three-dimensional (3D) data has limited validation to isolated structures, leaving whole-organism networks unexplored. Here, we developed a computational pipeline for whole-organism 3D imaging to reconstruct the complete vascular and nervous systems of rhesus macaque, mouse, and turtle embryos. Our analysis reveals that both networks share structural principles, including binary branching and scale-invariant bifurcation geometry, maintained across species and throughout development. Yet, from these shared rules emerge fundamentally different architectures. Vasculature exhibits fractal topology with a fractal dimension [~]3, forming space-filling trees that prioritize proximity to every cell in the body. Nervous system networks exhibit a fractal dimension [~]2, forming sheet-like arbors that prioritize electrical signal transmission. This architectural divergence originates from distinct biophysical constraints operating in bifurcations, where vascular junctions minimize energy expenditure while conserving fluid flow and nerve junctions maximize conduction velocity while conserving electrical current. These local optimization rules, iterated across generations, construct organism-wide networks governed by distinct physical constraints, revealing how evolution generated different solutions for fluid versus electrical transport.

developmental biology↗

bioRxiv2025

p53 preserves genome stability in dividing cells under hypo-osmotic stress

Cells respond to frequent osmotic stress to maintain structural integrity and function. Whereas acute volume regulation is well-known, the cellular response to prolonged osmotic stress and its long-term consequences remain poorly understood. In this study, we investigate how lasting hypo-osmotic stress influences cell growth and division and the associated cellular response. We observe that cells undergoing their first division under hypo-osmotic stress experience delayed mitotic entry, lengthened mitotic duration, elevated mitotic errors and aneuploidy formation. However, continued cell division is halted through a p53/p21-dependent G1 arrest. p53 activation occurs post-mitotically and is associated with hyper-condensed chromatin and impaired nuclear expansion in daughter cells after mitotic exit. We show that the altered nuclear size dynamics lead to nuclear accumulation of p53 and activation of downstream gene expression. These findings uncover a mechanosensitive, p53-mediated mechanism that safeguards genome integrity by suppressing erroneous mitosis under hypo-osmotic stress.

cell biology↗

bioRxiv2023

Cytoskeletal activation of NHE1 regulates cell volume and DNA methylation

Mammalian cells can rapidly respond to osmotic and hydrostatic pressure imbalances during an environmental change, generating large fluxes of water and ions that alter cell volume within minutes. While the role of ion pump and leak in cell volume regulation has been well-established, the potential contribution of the actomyosin cytoskeleton and its interplay with ion transporters is unclear. We discovered a cell volume regulation system that is controlled by cytoskeletal activation of ion transporters. After a hypotonic shock, normal-like cells (NIH-3T3, MCF-10A, and others) display a slow secondary volume increase (SVI) following the immediate regulatory volume decrease. We show that SVI is initiated by hypotonic stress induced Ca2+ influx through stretch activated channel Piezo1, which subsequently triggers actomyosin remodeling. The actomyosin network further activates NHE1 through their synergistic linker ezrin, inducing SVI after the initial volume recovery. We find that SVI is absent in cancer cell lines such as HT1080 and MDA-MB-231, where volume regulation is dominated by intrinsic response of ion transporters. A similar cytoskeletal activation of NHE1 can also be achieved by mechanical stretching. On compliant substrates where cytoskeletal contractility is attenuated, SVI generation is abolished. Moreover, cytoskeletal activation of NHE1 during SVI triggers nuclear deformation, leading to a significant, immediate transcriptomic change in 3T3 cells, a phenomenon that is again absent in HT1080 cells. While hypotonic shock hinders ERK-dependent cell growth, cells deficient in SVI are unresponsive to such inhibitory effects. Overall, our findings reveal the critical role of Ca2+ and actomyosin-mediated mechanosensation in the regulation of ion transport, cell volume, transcriptomics, and cell proliferation.

biophysics↗

bioRxiv2022

Cells in the Polyaneuploid Cancer Cell (PACC) state have increased metastatic potential

Although metastasis is the leading cause of cancer deaths, it is quite rare at the cellular level. Only a rare subset of cancer cells ([~]1 in 1.5 billion) can complete the entire metastatic cascade: invasion, intravasation, survival in the circulation, extravasation, and colonization (i.e. are metastasis competent). We propose that cells engaging a Polyaneuploid Cancer Cell (PACC) phenotype are metastasis competent. PACCs are enlarged, non-dividing cells with increased genomic content that form in response to stress. Single-cell tracking using time-lapse microscopy reveals that PACCs are more motile than nonPACCs. Additionally, PACCs exhibit increased capacity for environment-sensing and directional migration in chemotactic environments, predicting successful invasion. Magnetic Twisting Cytometry and Atomic Force Microscopy reveal that cells in the PACC state display hyper-elastic properties like increased peripheral deformability and maintained peri-nuclear cortical integrity that predict successful intravasation and extravasation. Furthermore, four orthogonal methods reveal that PACCs have increased expression of Vimentin, a known hyper-elastic biomolecule. Lastly, anoikis-resistance assays and detection of PACCs in the blood of a patient with metastatic castrate-resistant prostate cancer using a selection- free circulating tumor cell detection platform reveal that PACCs are capable of surviving in the circulation. Taken together with the knowledge that PACCs are capable of eventual depolyploidization and progeny formation (as a potential route to colonization), these data support PACCs as candidate metastasis-competent cells worthy of further analysis.

cancer biology↗

bioRxiv2021

The Correlation Between Cell and Nucleus Size is Explained by an Eukaryotic Cell Growth Model

In eukaryotes, the cell volume is observed to be strongly correlated with the nuclear volume. The slope of this correlation depends on the cell type, growth condition, and the physical environment of the cell. We develop a computational model of cell growth and proteome increase, incorporating the kinetics of amino acid import, protein/ribosome synthesis and degradation, and active transport of proteins between the cytoplasm and the nucleoplasm. We also include a simple model of ribosome biogenesis and assembly. Results show that the cell volume is tightly correlated with the nuclear volume, and the cytoplasm-nucleoplasm transport rates strongly influences the cell growth rate as well as the cytoplasm/nucleoplasm ratio. Ribosome assembly and the ratio of ribosomal proteins to mature ribosomes also influence the cell volume and the cell growth rate. We find that in order to regulate the cell growth rate and the cytoplasm/nucleoplasm ratio, the cell must optimally control groups of kinetic parameters together, which could explain the quantitative roles of canonical growth pathways. Finally, using an extension of our model and single cell RNAseq data, it is possible to construct a detailed proteome distribution, provided that a quantitative cell division mechanism is known. Author summaryWe develop computational model of cell proteome increase and cell growth to compute the cell volume to nuclear volume ratio. The model incorporates essential kinetics of protein and ribosome synthesis/degradation, and their transport across the nuclear envelope. The model also incorporates ribosome biogenesis and assembly. The model identifies the most important parameters in determining the cell growth rate and the nucleoplasm/cytoplasm ratio, and provides a computational starting point to construct the cell proteome based on the RNAseq data.

cell biology↗

bioRxiv2019

Trans-epithelial Fluid Pumping Performance of Renal Epithelial Cells and Mechanics of Cystic Expansion

Using a novel microfluidic platform to recapitulate fluid absorption activity of kidney cells, we report that renal epithelial cells can actively generate hydraulic pressure gradients across the epithelium. The fluidic flux declines with increasing hydraulic pressure until a stall pressure, at which the fluidic flux vanishes--in a manner similar to mechanical fluidic pumps. The developed pressure gradient translates to a force of 50-100 nanoNewtons per cell. For normal human kidney cells, the fluidic flux is from apical to basal, and the pressure is higher on the basal side. For human polycystic kidney disease (PKD) cells, the fluidic flux is reversed from basal to apical with a significantly higher stall pressure. Molecular studies and proteomic analysis reveal that renal epithelial cells are highly sensitive to hydraulic pressure gradients, developing different expression profiles and spatial arrangements of ion exchangers and the cytoskeleton in different pressure conditions. These results, together with data from osmotic and pharmacological perturbations of fluidic pumping, implicate mechanical force and hydraulic pressure as important variables during morphological changes in epithelial tubules, and provide further insights into pathophysiological mechanisms underlying the development of high luminal pressure within renal cysts.

biophysics↗

bioRxiv2018

Transition from actin-driven to water-driven cell migration depends on external hydraulic resistance

In vivo, cells can reside in diverse physical and biochemical environments. For example, epithelial cells typically live in a two-dimensional (2D) environment while metastatic cancer cells can move through dense three-dimensional (3D) matrices. These distinct environments impose different kinds of mechanical forces on cells, and thus potentially can influence the mechanism of cell migration. For example, cell movement on 2D flat surfaces is mostly driven by forces from focal adhesion and actin polymerization, while in confined geometries, it can be driven by water permeation. In this work, we utilize a two-phase model of the cellular cytoplasm, where the mechanics of the cytosol and the F-actin network are treated on an equal footing. Using conservation laws and simple force balance considerations, we are able to describe the contribution of water flux, actin polymerization and flow, and focal adhesions to cell migration in both 2D surfaces and in confined spaces. The theory shows how cell migration can seamlessly transition from a focal adhesion- and actin-based mechanism on 2D surfaces to a water-based mechanism in confined geometries.

cell biology↗

bioRxiv2018

Electromechanics and Volume Dynamics in Non-excitable Tissue Cells

Cell volume regulation is fundamentally important in phenomena such as cell growth, proliferation, tissue homeostasis and embryogenesis. How the cell size is set, maintained, and changed over a cells lifetime is not well understood. In this work we focus on how the volume of non-excitable tissue cells is coupled to the cell membrane electrical potential and the concentration of membrane-permeable ions in the cell environment. Specifically, we demonstrate that a sudden cell depolarization using the whole cell patch clamp results in a 30 percent increase in cell volume, while hyperpolarization results in a slight volume decrease. We find that cell volume can be partially controlled by changing the chloride or the sodium/potassium concentrations in the extracellular environment while maintaining a constant external osmotic pressure. Depletion of external chloride leads to a volume decrease in suspended HN31 cells. Introducing cells to a high potassium solution causes volume increase by up to 50%. Cell volume is also influenced by cortical tension: actin depolymerization leads to cell volume increase. We present an electrophysiology model of water dynamics driven by changes in membrane potential and in the concentration of permeable ions in the cell surrounding. The model quantitatively predicts that the cell volume is determined by the total amount of intracellular ion and protein content.

biophysics↗

bioRxiv2017

Role of Membrane-tension Gated Ca Flux in Cell Mechanosensation

Eukaryotic cells are sensitive to mechanical forces that they experience from the environment. The process of mechanosensation is complex, and involves elements such as the cytoskeleton and active contraction from myosin motors. Ultimately, mechanosensation is connected to changes in gene expression in the cell, or mechanotransduction. While the involvement of the cytoskeleton in mechanosensation is known, processes upstream to cytoskeletal changes is unclear. In this paper, using a microfluidic device that mechanically compresses live cells, we demonstrate that calcium currents and membrane tension-sensitive ion channels directly signals to the Rho GTPase and myosin contraction. In response to membrane tension changes, cell actively regulates cortical myosin contraction to balance external forces. The process is captured by a mechanochemical model where membrane tension, myosin contraction and the osmotic pressure difference between the cytoplasm and extracellular environment are connected by mechanical force-balance. Finally, to complete the picture of mechanotransduction, we find that the tension-sensitive transcription factor YAP translocates from the nucleus to the cytoplasm in response to mechanical compression.

cell biology↗