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Physical Forces and Collective Cell Migration in Development and Disease

Speaker: Alexandra Piotrowski-Daspit
Series: Final Public Oral Examinations
Location: 307 Hoyt Laboratory
Date/Time: Monday, May 2, 2016, 1:00 p.m. - 2:30 p.m.

Collective cell migration is a key driver of tissue remodeling during development, wound healing, and cancer invasion. However, the mechanisms cells employ to move cohesively and the influence of the physical microenvironment on collective behavior have not been fully elucidated. Using two different engineered three-dimensional (3D) culture models, we show that cells require mechanical sensing to migrate collectively and that extrinsic physical forces in their microenvironment can influence the migratory phenotype. We conclude that physical forces and biomechanics play a vital role in collective migration, both in development and disease contexts.

To study the physical mechanisms of collective migration in mammary gland branching morphogenesis, we used 3D engineered tissues embedded in collagen, a fibrous extracellular matrix (ECM) protein found in the natural cellular microenvironment. We show directly and quantitatively that collective migration occurs via a dynamic pulling mechanism, with pericellular matrix alignment preceding translocation. Tensile forces increase at the invasive front of cohorts, serving a physical role and a regulatory one by conditioning the cells and matrix for further extension. These forces elicit mechanosensitive signaling within the leading edge and align the ECM, creating microtracks critical for migration. Cell movements are highly correlated and in phase with ECM deformations. Migrating cohorts use spatially localized, long-range forces and consequent matrix alignment to navigate the ECM.

We also determined how an extrinsic physical force in the microenvironment of solid tumors, elevated interstitial fluid pressure (IFP), influences collective cancer invasion. Elevated IFP is a characteristic feature of solid tumors; IFP rises steeply beyond the tumor periphery and plateaus at values as high as 50 mm Hg above a normal value of 0 mm Hg, resulting in outward fluid flow from the tumor core towards the periphery. We used a 3D engineered model of a human breast tumor to probe the effects of IFP on collective invasion. We found that IFP influences the motility and invasive behavior of cancer cells by regulating the expression of genes associated with migratory behavior (epithelial-mesenchymal transition (EMT) genes). The expression levels of these markers are both necessary and sufficient to drive invasive behavior in response to IFP.