Biology subjects

Si, B. R.

Publications and source records attributed to Si, B. R..

3 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↗

bioRxiv2025

Anionic Lipid Trafficking and Cell Mechanics RegulateMembrane Electrical Potential in Non-Excitable Tissue Cells

1The membrane potential of eukaryotic cells, classically described by the Goldman-Hodgkin-Katz model, is conventionally attributed to the steady-state balance of transmembrane ionic fluxes. Here, we demonstrate that non-excitable cells maintain stable, spatially heterogeneous membrane voltage gradients. Using the ratiometric voltage indicator JEDI-2P-cyOFP1, we quantitatively map membrane potential in live cells and find that cellular protrusions are consistently depolarized, whereas lateral membrane regions are hyperpolarized. These voltage gradients strongly correlate with anisotropic distributions of anionic lipids, including phosphatidylserine (PS) and phosphatidylinositol 3,4,5-trisphosphate (PIP3). Perturbation of cytoskeletal integrity, the ion exchanger NHE1, or vesicular trafficking disrupts both voltage anisotropy and lipid polarization, revealing an uncharacterized electromechanical regulatory mechanism. Moreover, membrane potential dynamically responds to cell shape, substrate stiffness, external electric fields, and cell cycle progression. To account for these phenomena, we develop a quantitative model that integrates ionic fluxes and lipid charge distributions, thereby explaining the emergence of voltage gradients. This framework establishes that membrane potential is governed not solely by ionic currents but also by lipid dynamics and mechanical signaling. Collectively, these findings identify membrane voltage as a global integrator of electrochemical and mechanical cues in eukaryotic cells.

biophysics↗

bioRxiv2023

Serine synthesis pathway upregulated by E-cadherin is essential for the proliferation and metastasis of breast cancers

The loss of E-cadherin (E-cad), an epithelial cell adhesion molecule, has been implicated in the epithelial-mesenchymal transition (EMT), promoting invasion and migration of cancer cells and, consequently, metastasis. However, recent studies have demonstrated that E-cad supports the survival and proliferation of metastatic cancer cells, suggesting that our understanding of E-cad in metastasis is far from comprehensive. Here, we report that E-cad upregulates the de novo serine synthesis pathway (SSP) in breast cancer cells. The SSP provides metabolic precursors for biosynthesis and resistance to oxidative stress, critically beneficial for E-cad-positive breast cancer cells to achieve faster tumor growth and more metastases. Inhibition of PHGDH, a rate-limiting enzyme in the SSP, significantly and specifically hampered the proliferation of E-cad-positive breast cancer cells and rendered them vulnerable to oxidative stress, inhibiting their metastatic potential. Our findings reveal that E-cad adhesion molecule significantly reprograms cellular metabolism, promoting tumor growth and metastasis of breast cancers.

cancer biology↗