Abstract With the recent enormous progress in uncovering the roles of YAP/TAZ in cell proliferation, differentiation, tissue organization and tumorgenesis, the crosstalk of YAP/TAZ mechanical regulators and the Hippo pathway regulators (the cell-cell adhesion) remains largely elusive. To bridge the current gap in our understanding, we present a computational model predicting YAP/TAZ activity depending on ECM mechanical properties, cell-cell adhesions, and more importantly, the crosstalk between the two. We propose a mechanism of the interaction between LIMK and LATS to explain the unresolved synergistic effect of YAP/TAZ activity between the mechano-sensing and the Hippo pathways. Using this computational model, we are able to analyze the synergistic effects of YAP/TAZ driven by the LIMK-LATS mechanism or by the AMOT mechanism, which is another key candidate for the crosstalk. Cancer cell lines that have downregulated E-cadherin expression overcoming the LATS-dependent YAP/TAZ contact inhibition regulation, and the mechanical sensing of YAP/TAZ serves as an important checkpoint for regulating tumor progression. We are able to quantitatively predict the YAP/TAZ activity as a function of mechanical ECM properties (stiffness response function) in these systems. Our model aims to bridge the gap by including mechano-to-biochemical signal conversion by adhesion molecules, intracellular signal transmission, cytoskeleton dynamics, and regulation of effectors relevant to directing transcriptional programs, such as YAP/TAZ activity. Such an integrated molecular model predicts effects of molecular inhibitors or changes in mechanical propertiesin silico, and the difference in 2D and 3D. For example, adhesion molecules such as FAK can shift the stiffness response function horizontally, such that FAK overexpression rescues YAP/TAZ activity in soft environments. The model also predicts that the sensitivity of YAP/TAZ activity to ECM mechanical properties is higher than the one of SRF/MAL, which is another important regulator of differentiation and regulated by cytoskeleton dynamics. Overall, our model provides a novel platform of studying YAP/TAZ activity in the context of integrating different signaling pathways. This platform can be used to gain new fundamental insights into the role of key molecular and mechanical regulators on development, tissue engineering or tumor progression. Citation Format: Meng Sun, Fabian Spill, Muhammad Zaman. Modeling and analysis of YAP/TAZ activity integrating mechanosensing and the Hippo pathway. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr A34.