Biology subjects

Yow, I.

Publications and source records attributed to Yow, I..

4 recordsLinked to original sources

bioRxiv2023

Co-evolution of spheroid fluidization and mechanical fracture in a morphogenic cascade

Cells migrate and invade tissues during development, immune responses, and cancer. Collective invasion is generally understood to be driven by invading cells unjamming and pushing through barriers such as the extracellular matrix and surrounding tissues. Whether these barriers actively contribute to invasion remains unclear. Using ovarian adenocarcinoma spheroids invading mesothelium derived from benign pleural effusions as an experimental model, combined with modelling, we examine invasion across molecular to multicellular scales. We identify intercellular integrin adhesions linking invasive leader cells to the tissue barrier, triggering apical constrictions within the barrier. This constriction shrinks cell-cell contacts, leading to barrier rupture. Thus, the tissue barrier plays a mechanically active role in invasion. Rather than cells pushing through, we find that coordinated subcellular contractility between the invading leader cell and the barrier drives barrier tensile rupture and invasion, independent of a jamming transition. Together, our findings challenge prevailing paradigms of collective cell invasion.

cell biology↗

bioRxiv2023

Natural Killer cell contractility and cytotoxicity is driven by TLR3 agonist-mediated TAZ cytoplasmic sequestration

The evolutionarily conserved YAP/TAZ mechano-responsive transcription cofactors regulate development and tumorigenesis. Here, we show for the first time that human natural killer (NK) cells specifically express TAZ but not YAP, and TAZ serves to limit NK cytotoxicity. The TLR3 agonist, hiltonol, was able to trigger cytoplasmic sequestration of TAZ, which increased NK cytotoxicity. Mechanistically, a low dose of hiltonol enhanced the intracellular contractility of NK cells accompanied by an increase in active RhoA and myosin light chain phosphorylation, conceivably through an increase in ERK1/2 activation-dependent ROS production. Importantly, we showed that the dissociation of LATS1 from actin upon activation of contractility, is required to sequester TAZ in the cytoplasm. Functionally, hiltonol also reduced the NK cell surface inhibitory receptors, KIR3DL1 through c-Myc inhibition and PD-1 through enhanced contractility. Direct inhibition of c-Myc promoted NK cytotoxicity against K562 lymphoblast. We corroborated our findings by coculturing hiltonol-pretreated NK cells with breast and lung cancer cells, and demonstrated increased NK-mediated cancer killing, which conceivably occurred via sequestration of TAZ to the cytoplasm which facilitated NK cytotoxicity. Our findings pave the way for ex vivo rejuvenation of NK cells for in vivo immunotherapies, which could involve a cocktail of hiltonol and c-Myc inhibitor.

cell biology↗

bioRxiv2022

Mechanical stress driven by rigidity sensing governs epithelial stability

Epithelia act as a barrier against environmental stress and abrasion and in vivo they are continuously exposed to environments of various mechanical properties. The impact of this environment on epithelial integrity remains elusive. By culturing epithelial cells on 2D hydrogels, we observe a loss of epithelial monolayer integrity through spontaneous hole formation when grown on soft substrates. Substrate stiffness triggers an unanticipated mechanical switch of epithelial monolayers from tensile on soft to compressive on stiff substrates. Through active nematic modelling, we find unique patterns of cell shape texture called nematic topological defects that underpin large isotropic stress fluctuations at certain locations thereby triggering mechanical failure of the monolayer and hole opening. Our results show that substrate stiffness provides feedback on monolayer mechanical state and that topological defects can trigger stochastic mechanical failure, with potential application towards a mechanistic understanding of compromised epithelial integrity in bacterial infection, tumor progression and morphogenesis.

biophysics↗

bioRxiv2021

Mechanics defines the spatial pattern of compensatory proliferation

The number of cells in tissues is tightly controlled by cell division and cell death, and misregulation of cell numbers could lead to pathological conditions such as cancer. To maintain cell numbers in a tissue, a cell elimination process named programmed cell death or apoptosis, stimulates the proliferation of neighboring cells. This mechanism is called apoptosis-induced compensatory proliferation, which was originally reported more than 40 years ago. While only a limited number of the neigboring cells need to divide to compensate for apoptotic cell loss, the mechanisms that select cells for undergoing division remain an open question. Here we found that the spatial inhomogeneity in mechanotransduction through a growth-promoting transcription co-activator Yes-associated protein (YAP) in the neighboring tissue, accounts for the inhomogeneity of compensatory proliferation. Such inhomogeneous mechanotransduction arises from the combination of the non-uniform distribution of nuclear size, which is inherent in tissues, and the non-uniform pattern of mechanical force applied to the neighboring cells upon apoptosis. Our findings from a mechanical perspective complement the current biochemical understanding of compensatory growth and provide additional insights into cellular functions of how tissue precisely maintains its homeostasis.

cell biology↗