Research
How are molecular and mechanical signals translated across time and length scales to organize and drive the collective behaviors that maintain and shape human tissues?
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Our lab broadly investigates how biochemical and mechanical signals are coordinated across biological scales (molecules to cells to tissues) to maintain normal tissue structure or drive pathology. Our efforts are primarily focused in the experimental arenas of cardiovascular disease and solid tumors (e.g. breast and oral cancers).
At the molecular level, we are experts in elucidating new mechanisms underlying adhesion biology, the interactions of cells with their neighbors and their microenvironment. We study how core adhesion molecules like cadherins and integrins integrate and orchestrate chemical and mechano-signaling to specify multicellular behavior, proper organization and differentiation of complex tissues, as well as facilitate the progression of disease. At the cellular level, we develop and apply quantitative imaging and molecular tools (optogenetics, synthetic biology, microenvironment biomaterials/patterning) that allow us to measure, direct, and perturb cellular behaviors to understand how collective decisions initiate and propagate within tissues. At the tissue level, we engineer organotypic 3D microfluidic models of human tissues with defined architectures and microenvironments in vitro that permit the simulation, molecular dissection, and quantitative analysis of in vivo-like morphogenic processes. We are working to combine these platforms with organoid systems, unbiased proteomics, and single-cell analyses to build spatio-temporal road maps of human development and disease. |
regulation of morphogenesis, fate, and pathogenesis by cell adhesion
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We recently identified an exciting new mechanism linking two essential processes developed at the start of the evolution of multicellular organisms, cadherin cell-cell adhesion and Notch receptor signaling (Polacheck and Kutys et al. Nature). Current efforts are focused on dissecting the reciprocal nature of these interactions, their role in controlling multicellular communication and mechanobiology, and defining significance in the context of tumor suppression and in the formation of vascular networks.
Using proximity-ligation mass spectrometry, we have identified a host of candidate proteins controlling plasma membrane organization, mechanical signaling, and downstream growth/fate signaling at cell-cell contacts in vascular endothelial cells and mammary epithelia. We are evaluating the morphogenic significance of these interactions in our engineered tissue systems, as well as using these insights to inform biomaterials design that mimic cell-cell adhesion for 3D tissue patterning and regeneration. |
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Single cell origins of collective behavior
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How emergent collective behaviors arise within a tissue is poorly understood. In the context of cancer, recurring human mutations have been identified but how they contribute to the morphogenic behaviors that underlie tumor progression is not known. Shockingly, it isn't known how, or even whether, targeted drugs impact the biology of tumor cells at specific stages of progression in a natural 3D environment!
Using organotypic 3D human tissue models along with precision tools such as optogenetics, syn bio, and microenvironmental patterning, we are able to induce genetic and molecular changes to an individual cell within a structured 3D tissue and subsequently measure, direct, and perturb cellular behaviors to ultimately study the dynamics, mechanics, and governing principles of collective 3D behaviors (Kutys and Polacheck et al. Nature Communications). Our current efforts are focused in the context of breast and oral cancers. |
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spatiotemporal Cell and mOlecular Road Maps of DEvelopment and Disease
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The tissue-scale morphodynamics that shape developing and regenerating organs are orchestrated by heterogeneous cell populations with precise spatial and temporal control. With the booming advent of stem-cell derived organoid systems that provides an avenue towards in vivo organ complexity, we are working to engineer new microphysiological systems that provide architecture and reproduciblity to organoid systems and permit the controlled induction of 3D tissue morphogenic behaviors, such as branching morphogenesis. It is our goal to combine such platforms with live-cell multiplexed barcoding methods and single cell RNA sequencing to build a mechanistic molecular and cellular road map of development and disease in complex human tissues ex vivo.
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Vascularized organoid systems for biological discovery and REGENERATIVE medicine
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A major hurdle in the scaling of organoid systems in vitro and in the development of tissue engineered therapies for regenerative medicine is the incorporation of stable vasculature. The vasculature not only systemically provides nutrients and removes wastes from tissues, but also actively signals to resident paraenchymal and stromal cells to promote tissue maturity and homeostasis in an organ-specific manner. We are building microfluidic tissue models that allow for mechanistic investigation into these heterotypic juxtacrine interactions and paracrine signaling. Through active collaborations, we are building 3D in vitro vascularized networks supporting iPSC-derived tissues and patient-derived breast cancer organoids systems to be used for biological discovery, personalized medicine screening, and regenerative medicine.
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