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Leader cells direct collective migration through sensing cues in their microenvironment to determine migration direction. The mechanism by which leader cells sense the mechanical cue of organized matrix architecture culminating in a mechanical response is not well defined. In this study, we investigated the effect of organized collagen matrix fibers on leader cell mechanics and demonstrate that leader cells protrude along aligned fibers resulting in an elongated phenotype of the entire cluster. Further, leader cells show increased mechanical interactions with their nearby matrix compared to follower cells, as evidenced by increased traction forces, increased and larger focal adhesions, and increased expression of integrin-α2. Together our results demonstrate changes in mechanical matrix cues drives changes in leader cell mechanoresponse that is required for directional collective migration. Our findings provide new insights into two fundamental components of carcinogenesis, namely invasion and metastasis. 

Cellular response to stimulation governs tissue scale processes ranging from growth and development to maintaining tissue health and initiating disease. To determine how cells coordinate their response to such stimuli, it is necessary to simultaneously track and measure the spatiotemporal distribution of their behaviors throughout the tissue. Here, we report on a novel SpatioTemporal Response AnalysisIN Situ(STRAINS) tool that uses fluorescent micrographs, cell tracking, and machine learning to measure such behavioral distributions. STRAINS is broadly applicable to any tissue where fluorescence can be used to indicate changes in cell behavior. For illustration, we use STRAINS to simultaneously analyze the mechanotransduction response of 5000 chondrocytes—over 20 million data points—in cartilage during the 50 ms to 4 hours after the tissue was subjected to local mechanical injury, known to initiate osteoarthritis. We find that chondrocytes exhibit a range of mechanobiological responses indicating activation of distinct biochemical pathways with clear spatial patterns related to the induced local strains during impact. These results illustrate the power of this approach.