Epidermal growth factor gradient sensing by epithelial cells is a crucial process in development and many disease processes such as cancer metastasis. Understanding the basic principles of this sensing would enable us to intervene in disease processes that involve directional cell motion by pharmacologically targeting the communication rather than the within-cell regulation, and it can stimulate a novel direction for therapeutics. Through a combination of novel experimental and theoretical approaches, this project will characterize advantages and limitations of multicellular gradient sensing in breast epithelial tissue in a mouse model. It will explore the fundamental physical limits on collective gradient sensing and will establish to which extent the size of multicellular ensembles aids their sensory precision. The project will also support synergistic curriculum development efforts on the interface of physics and biology at three research universities, on levels from introductory undergraduate to advanced graduate. It will provide research and broader career training opportunities for undergraduate and graduate students and postdocs, including minority students. The PIs will engage elementary school students in science projects and they will reach out to the general public disseminating their research findings at the Atlanta Science Festival.
Cells in multicellular organisms rarely act alone in responding to external signals, but little is known about behaviors that emerge from their multicellular, collective communication and action. In particular it is unknown if multicellular ensembles can collectively sense chemical gradients in ways that take advantage of such ensembles spanning substantial ranges of the chemo-attractant concentration. The PIs' experiments with multicellular ensembles of breast epithelial cells exposed to gradients of epidermal growth factor suggest that these cells can sense gradients collectively and that collectively cells respond to gradients that are far smaller than those sensed by individual cells. This multicellular information processing is fundamentally distinct from, and not simply reducible to, sensory processes in isolated cells. The PIs will establish theoretically and verify experimentally the fundamental physical limits on the precision of gradient sensing by multicellular ensembles. These limits containing contributions from the extrinsic ligand stochasticity and from the intrinsic noise in communicating the measurements made by distant cells in a multicellular group to individual cells within the group will be characterized. The PIs will develop computational methods to analyze precision of biological information processing in collective, nonlinear phenomena, such as epithelial tissue rearrangement, which will be applicable broadly in other biophysical contexts.
