Bimodal sensing of guidance cues in mechanically distinct microenvironments

Abstract

Contact guidance due to extracellular matrix architecture is a key regulator of carcinoma invasion and metastasis, yet our understanding of how cells sense guidance cues is limited. Here, using a platform with variable stiffness that facilitates uniaxial or biaxial matrix cues, or competing E-cadherin adhesions, we demonstrate distinct mechanoresponsive behavior. Through disruption of traction forces, we observe a profound phenotypic shift towards a mode of dendritic protrusion and identify bimodal processes that govern guidance sensing. In contractile cells, guidance sensing is strongly dependent on formins and FAK signaling and can be perturbed by disrupting microtubule dynamics, while low traction conditions initiate fluidic-like dendritic protrusions that are dependent on Arp2/3. Concomitant disruption of these bimodal mechanisms completely abrogates the contact guidance response. Thus, guidance sensing in carcinoma cells depends on both environment architecture and mechanical properties and targeting the bimodal responses may provide a rational strategy for disrupting metastatic behavior.

Engineering T cells to enhance 3D migration through structurally and mechanically complex tumor microenvironments

“…To generate soft to stiff nanopatterned platforms we engineered high definition nanotextured polyacrylamide gel (PAAG) surfaces with Hookean elasticity and shear moduli of G'=2. 3, 8.6, 16, 50, and ≫1,000 kPa (Tabdanov et al, 2018a(Tabdanov et al, , 2018b, and functionalized surfaces with either ICAM1 or ECM, and utilized these platforms to dissect architectural and mechanical regulation of T phenotypic plasticity and cell migration.…”

“…Indeed, the complex stromal reaction in solid tumors can limit access and effective distribution of T cells creating antitumor immunityfree sanctuaries (Elahi-Gedwillo et al, 2019;Hartmann et al, 2014;Kuczek et al, 2019;Salmon et al, 2012;Stromnes et al, 2017). Furthermore, many solid tumors are rich with aligned extracellular matrix (ECM) networks (Best et al, 2019;Provenzano et al, 2006;Ray et al, 2017a) , which provide contact guidance for carcinoma cells (Provenzano et al, 2006(Provenzano et al, , 2008Tabdanov et al, 2018aTabdanov et al, , 2018b, and can also direct migration of infiltrated T cells in solid tumors (Hartmann et al, 2014;Salmon et al, 2012;Wolf et al, 2003). Yet, our understanding of how native and engineered T cells migrate through mechanically complex tumor microenvironments (TMEs) is quite incomplete.…”

Distinct roles of nonmuscle myosin II isoforms for establishing tension and elasticity during cell morphodynamics

“…We produced cross-shaped FN-micropatterns via microcontact printing, which restrict FA formation to the pattern but still provide a sufficient adhesive area for the spreading of U2OS cells (see methods section for details). U2OS WT and all KO cell lines adapted their shape to the pattern and gained a striking phenotype with concave, inward bent actin arcs that line the cell contour as previously described for various cell types (Figure 2) (Bischofs et al, 2008;Brand et al, 2017;Kassianidou et al, 2019;Labouesse et al, 2015;Tabdanov et al, 2018;Thery et al, 2006). These arcs bridge passivated substrate areas and have a circular shape.…”

Mechanochemical Patternable ECM‐Mimetic Hydrogels for Programmed Cell Orientation

“…[ 34 ] In this context, several fundamental studies are beginning to unfold the decoupled influence of biophysical and biochemical stimuli on contact guidance cues. [ 35 ] Still, native matrices present a seamless combination of biochemical and topographical features in their bioarchitectures which has remained elusive in hydrogel design. [ 36 ] Recently, it has been increasingly recognized that natural tissues and collagen matrices are viscoelastic with mechanical plasticity, irreversibly deforming in response to force.…”