CAREER: Building a Theory of Collective Cellular Sensing with Applications to Morphogenesis, Chemotaxis, and Metastasis

Theoretical and experimental work from the past forty years has established that the sensory precision of single cells approaches the limits of what is physically possible. However, experiments within the past ten years suggest that sensory precision is enhanced even further when cells interact. These experiments are fascinating and raise many fundamental questions about sensory cooperation, information sharing, and collective behavior.

This project will address this problem by developing a comprehensive theory of collective cellular sensing. The project focuses on three examples from cell biology - morphogenesis in Drosophila, chemotaxis in E. coli, and metastasis of breast cancer and melanoma cells, where experiments suggest that cell-cell communication enhances sensing, but the mechanism of enhancement is poorly understood.

In each case, a theoretical framework will be developed based on known features of the system and the framework will be validated using experimental data. The research, educational, and outreach activities are designed in a strongly interconnected manner to increase the broader impact of the work. Graduate and undergraduate students will directly perform the research and disseminate it through publications and conferences.

The research will be integrated into education via an inquiry-based teaching module and cross- disciplinary units in the PI's graduate and undergraduate courses. Designed and piloted in collaboration with graduate students, the departmental outreach coordinator, and a local high school teacher, the activity will be delivered on campus, at an Indiana middle school serving underrepresented students, and at a state-wide and a national education conference, thereby reaching thousands of middle and high school students, particularly underrepresented students.

Special focus is placed on developing and assessing knowledge of microbiology, microscopy, statistics, and number sense.

Sensory precision is crucial during development because cells determine their fates by sensing concentrations of molecules called morphogens. Recent experiments suggest that short-range cell-cell communication may help increase the precision of morphogen profile formation and the establishment of cell fate boundaries, but the mechanisms are still unclear.

The PI will develop a theory of concentration sensing with short- range communication, validate it using previous experiments in Drosophila and zebrafish embryos, and make predictions for future morphogenesis experiments. In addition the PI will build a theory of long-range communication and apply it to bacterial chemotaxis. Bacteria move toward favorable environments by sensing gradients in attractant concentrations, a process called chemotaxis.

Recent experiments suggest that chemotaxis is enhanced by long-range cell-cell communication, but the enhancement mechanism is unknown. To address this question the PI will develop a theory of gradient sensing and chemotaxis with long-range communication, validate it using previous experiments on E. coli bacteria, and make predictions for future chemotaxis experiments, including those of a collaborating lab.

The PI will also build a theory of self-communication and apply it to cancer metastasis. Many cancer cells spread to other parts of the body, or metastasize, by sensing lymphatic flow. Recent experiments suggest that these cells sense flow by self-communication (releasing a molecule that they also detect), but the details of this mechanism are still poorly understood and the PI will develop a theory of flow sensing via self-communication, validate it using previous experiments on breast cancer and melanoma cells, and make predictions for future cancer biology experiments.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.