Spatial Patterning in the Progressing Tumor - The Role of Notch

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Cancer becomes deadly when tumor cells become motile and begin to spread throughout the patient's body. To become motile, cells must undergo radical changes in their composition and behavior, the so-called epithelial-mesenchymal transformation (EMT). These radical changes arise as the network of genes controlling the state of the cell transitions from one type of stable fate to another. This project details a joint theory-experiment physics-biology effort to study how EMT is coordinated in space and time by chemical signals passed among the tumor cells. The specific focus here is on the Notch signaling pathway. This pathway has been studied extensively for its role in developmental biology and has been implicated indirectly in cancer, but has never been studied systematically in this context. The hypothesis to be investigated is that this pathway can allow the formation of small clusters of cells that have undergone EMT together, and which thereafter travel as a collective en route to the establishment of a secondary tumor. If proven to be true, these ideas will shed light on the fundamental origins of metastasis and might in the future offer new strategies for both prognosis and treatment. Cell-cell interactions, both between tumor cells proper and between tumor and stromal cells, are known to be a key component of many solid tumors. The investigators will focus on how one of these interactions, that mediated by the Notch pathway, can coordinate cell phenotypes and can thereby control tumor progression. To accomplish this will require the use and extension of sophisticated theory techniques from the field of non-equilibrium pattern formation coupled to an experimental plan focused on pancreatic cancer cell lines to be studied in both 2d and 3d in vitro conditions, both without and with supporting cancer-associated fibroblasts. Of particular importance will be measuring spatial correlations of EMT state (and other known correlates) and comparing these to expectations based on different signaling assumptions. Iterating these experiments with increasingly realistic model-building and model-solving will allow for the creation of a quantitatively reliable picture for the collective behavior of the tumor, going well-beyond current individual cell approaches.This project is cofunded by the Physics of Living Systems Program in the Physics Division and the Molecular and Cellular Biosciences Division at NSF.