Quantitative analysis and predictions of multiplexed microenvironmental stimuli on tumor progression
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Microenvironmental stimuli are important in maintenance of homeostasis, development, and tumor progression. For example, in tumor tissues the collagen becomes abnormal when tumor advances, and this remodeling may potentially in turn impact cell fates and even malignancy. However, little has been investigated into how this matrix reorganization occurs and regulates cellular behaviors through intracellular signaling transduction. This also poses a challenging but important question regarding how cells dynamically integrate cell-cell and cell-matrix interactions to respond to this mechanical remodeling. Tumor microenvironment is multi-faceted and dynamic, and quantitative understanding of the feedback between the tumor and the microenvironment requires a high-dimensional quantitative analysis. To pursue these goals, we first developed a toolkit to precisely and reliably quantify matrix-based microenvironmental features during tumor progression. A collagen network dynamic model was also built to further study and predict the mechanical property changes during collagen remodeling in tumor expansion. The transcriptional regulators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) have been found as the most robust mechanosensors that tightly regulate malignant phenotypes and chemo-resistance in many cancers, however we have little knowledge of how they are regulated by multiplexed microenvironmental stimuli simultaneously. Here, we combined computational modeling with experimental evidence to examine how changes in matrix mechanical property regulate YAP/TAZ and related phenotypes integrating varying local cell densities and the integration signaling mechanism. The kinetic parameter estimation of our model suggests that the key mechanism in driving YAP/TAZ activation in the triple negative breast cancer MDA-MB-231 cell lines is the endogenous high contractility. Therefore, the matrix feature quantification, the collagen network mechanical predictions and integration mechanism of YAP/TAZ upstream signaling present a comprehensive knowledge of the role of collagen remodeling in cancer at different scales and time points. This study of platform enables potential treatment strategy exploration based on mechanical inhibition in cancer cells, and more importantly, the role of multiplexed microenvironment in tumor progression with the big data analysis.