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

Current topics (updated January 2023):

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.

Epithelial cell mechanobiology

Epithelial cells collectively grow, stretch, fold, and migrate to form tissue, sculpt organs, line interfaces, and heal wounds within the body. Their dysfunction can cause fibrosis and cancer metastasis. Cellular forces and matrix stiffness have been shown to alter collective cell migration and EMT phenotypes. Our ongoing work is exploring how matrix geometry alters epithelial response (migration, shape, EMT) and how these responses have effects across length scales (multicellular to subcellular and subnuclear).

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:

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

Our projects often involve:

fabrication of soft cell culture substrates
molecular biology assays
high resolution imaging
computational models

Funding Sources

Current Funding

NIH/NIGMS R35 MIRA R35GM128764 (Pathak)
NSF/CMMI 2209684 (Pathak)
NIH/NCI R01 R01CA254060 (Longmore, Pathak)
NIH/NINDS R01 R01NS111948 (Kroenke, Bayly)
NSF Center for Engineering Mechano-Biology 1548571

Completed funding

NIH/NIBIB Trailblazer (Pathak, Klechevsky)
Siteman Cancer Center (Pathak)
Mallinckrodt Foundation (Pathak)

Emerson Collective (Pathak)
American Cancer Society (Pathak)