Regulation of cell migration by biochemical and mechanical environmental cues

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Cell migration is a fundamental phenomenon that is critical for life of unicellular and multicellular organisms. Simple organisms, such as amebae, have to migrate to find food and to mate. Complexity of multicellular organisms, such as vertebrates, brings the necessity for individual cells and groups of cells to position themselves during developmental morphogenesis that is largely achieved through directed cell migration. In the adult, directed migration plays an important role in a wide range of physiological and pathological processes, including renewal of skin and intestinal epithelium, immune system function, and wound healing, as well as cancer metastasis and cardiovascular diseases.***Over the last two decades, immense progress has been made in understanding the complexity of mechanisms that regulate directed cell migration. This includes discovery of various extracellular cues such as biochemical gradients, mechanical forces, and gradients of extracellular matrix (ECM) stiffness and topology that guide migrating cells. Another key finding was identification of signaling pathways transducing individual environmental cues into directed cell movement. Despite this, much less is known about molecular mechanisms regulating directional cell movement in a tissue environment where multiple cues of different nature are presented simultaneously.***Here, we propose to reveal these mechanisms by using a combination of state-of-the-art biophysical techniques: synthetic hydrogels with tunable mechanical properties to mimic stiffness landscape of biological tissues and microfluidics to control local concentration of soluble biochemical cues. By coupling these approaches with quantitative live-cell imaging, and molecular analysis of intracellular signaling pathways we will reveal specific molecular players that integrate multiple cues, and direct cell migration in tissue environment.***The specific aims of this proposal include: (1) To determine the crosstalk between chemical and mechanical guidance cues in a novel in vitro model of directed cell migration; (2) To determine the molecular mechanisms mediating the crosstalk between chemical and mechanical guidance cues and directing cells in environments where multiple cues co-exist. This work will shed light on how biochemical cues regulate cell migration guided by physical gradients (ECM stiffness). It will also identify signaling pathways that integrate biochemical and mechanical guidance cues and dynamically regulate the cytoskeletal network to provide stereotypical cell behavior during crucial physiological or pathological processes, including tumor metastasis.**