Mechanotransduction – from how cells sense mechanical forces in different tissues to how these mechanical forces are transduced into biochemical signals – is an essential biological process in development, normal physiology and disease. Our research group in this exciting area is particularly interested in investigating the role of mechano-biological processes associated with cell-cell and cell-matrix interactions (e.g. topography, rigidity, dimensionality, etc.) in the regulation of collective cell migration and tissue morphogenesis within controlled microenvironments. Using a combination of various techniques, from live cell imaging analysis to nanotechnology with microrheological measurements, we have been generating interesting data suggesting that one of the most important factors distinguishing malignant from benign cells could be their ability to collectively invade and migrate towards blood vessels by physically interacting with the surrounding extracellular matrices. We combine in-chip live cell culture platforms with time-lapse live cell imaging or FRET (‘fluorescence’ resonance energy transfer) imaging of fluorescently-labeled mechanotransductive signaling proteins (so called “in-chip molecular live cell imaging”). Using these novel tools, our research involves quantitative characterization of the individual and collective behaviors of cancer cells from different stages of the malignant progression using microfabricated tumor tissue models. We particularly focus on analysis of signaling, migration and mechanical properties of highly malignant and invasive tumor cells (vs. benign cells) in glioblastomas, melanomas, and breast cancers. We recently developed a micro/nanofabricated collective migration assay as an enabling tool for analysis and control of cancer cell migration and invasion in a high-throughput, quantitative manner. Using these tools, we also explore the potential role of mechanical guidance in the regulation of tumor progression and invasion under the presence/absence of growth factor-induced signals, and test their biomedical implication by screening cytoskeletal and signal transduction pathways. The proposed high-throughput functional assay for cell migration is a transformative tool for personalized cancer therapy by virtue of its ability to 1) reveal molecular mechanisms of cancer cell invasion relevant to the contexts of specific cancers and 2) provide a functional assay to develop new therapies and ultimately inform patient-specific drug treatments. By experimenting with the nanotopographically-defined cell culture substrates (i.e. quasi 3D cell culture system) and tissue specific dECM bioinks, we are also investigating the role of ECM composition, structure, and mechanics on directed differentiation and functional maturation of cardiomyocytes from human pluripotent stem cells, and the biophysical and signaling mechanisms that underpin these processes. We utilize FRET biosensors, along with systems biology analysis techniques (e.g. mass spectrometry–based proteomics), in order to study the signaling mechanisms that translate exogenous mechanical cues to changes in gene and protein expression. Using this multifaceted approach, we aim to gain a greater understanding of the mechanisms that regulate complex interactions between stem cells and their local microenvironment (or niche), and how manipulation of these pathways can enable the functional maturation of human pluripotent stem cell-derived tissues. These works will provide insight into stem cell and developmental biology and the role of the cardiac microenvironment in controlling cardiac development and maturation in vitro.