Research

We study cellular mechanobiology in mechanically heterogeneous microenvironments by employing principles and methods from applied mechanics, biophysics, computational modeling, biomaterials science, and cell biology.

Memory-dependent cell migration

^{In developing organisms or in cancer, cells migrate from one environment to another. Although mechanosensing studies have shown that cells can sense and respond to their local mechanics, it is unclear whether they remember their past environments. We study novel processes of mechanical and environmental memory in cells by employing cross-disciplinary methods – theory to integrate proteomic, transcriptional, and epigenetic mechanosensing; predict memory-dependent cellular responses; memory-dependent cell migration; invasion due to matrix memory.}

Cell mechanosensing of matrix geometry

^{Epithelia often do not reside on flat, homogenous surfaces. Instead, they encounter tissue and surface heterogeneities due to confinements, defects, and aligned fibers in extracellular microenvironments. We use lithography, hydrogel synthesis, and modular matrix fabrication methods to make matrices of varying geometries and measure varying modes of epithelial migration and EMT. For example, we study how collectively migrating epithelial cells move into narrow confinements, navigate obstructions via cellular softening and fluidization, and migrate faster on aligned fibers by contractility stabilization.} 

Multiscale mechanotransduction in epithelia: from ECM to nucleoplasm

^{Cellular collectives sense extracellular cues in complex environments and communicate mechanotransductive signals between cells and into subcellular compartments. This can induce robust mechano-responses (migration, EMT). We study how matrix stiffness and leader positioning of cells triggers changes in nuclear condensate formation and composition of nucleoli (hubs for protein synthesis). Since mechanotransduction requires stiffness-sensitive gene expression, we also explore whether simultaneous expression of mechanoactivation promoter and suppressor genes via nuclear export inhibition complicates EMT and collective cell migration.}

Cellular and extracellular heterogeneities in cancer

^{During cancer progression there are cellular, mechanical (collagen fiber deposition and remodeling) and chemical (secreted factors) changes in the tumor stroma that promote tumor invasion and migration. We study how cancer associated fibroblasts (CAFs) and leader cells perform collagen remodeling to enable collective breast tumor invasion. Since cancer cells must move from stiff tumors to soft healthy tissue, we also ask whether they utilize mechanical memory of primary tumor to invade and whether they depth-sense into distant matrices.}

In previous projects, we have developed several novel methods:

• ^{finite element modeling of cellular and tissue contractility}
• ^{soft microchannels for single cell migration and epithelial-mesenchymal transition (EMT)}
• ^{modeling of stick-slip cell migration}
• ^{modeling of EMT and collective migration}
• ^{hydrogel-collagen layered matrices}
• ^{contiguous soft-stiff hydrogels to study cellular memory}
• ^{soft substrates with tunable collagen fiber length}
• ^{monolayer traction microscopy}
• ^{Atomic Force Microscopy (AFM) for cell and tissue stiffness.}

Through such approaches, we have discovered new cellular phenomena in soft environments that otherwise mimic healthy tissues:

• ^{cancer cells (breast and brain) migrate faster and undergo EMT in confined environments}
• ^{physical defects in basement membrane-like substrates induce EMT and cell invasion}
• ^{longer collagen fibers enhance cellular forces and collective cell streaming (despite soft matrices)}
• ^{leading edge positioning of cells promotes cancer-like nucleoli}
• ^{past stiff priming stores mechanical memory in cells and accelerates future migration on soft matrices}

fabrication of soft cell culture substrates

molecular biology assays

high resolution imaging

computational models