A multiscale approach to control cellular interactions in premalignant tissues

About This Grant

PROJECT SUMMARY The overarching goal of this project is to use physical science approaches to precisely manipulate interactions between multiple cell types in premalignant tissues in ways that restore normal tissue function. Our approach is based on our understanding that the form and function of normal tissues is determined by the physical and chemical interactions between the diverse cells that comprise them. Cancers arise when the controlling signals are corrupted by genomic or epigenomic changes. We propose here a multidisciplinary approach to chemically “adjust” interactions in precancerous tissues to restore normal tissue function. This is made possible by new analytical tools that allow precise elucidation of the molecular characteristics of each cell, the signals that each cell receives and their spatiotemporal responses to those signals, as well as the organization of normal and diseased tissues. Additionally, recent technological developments facilitate recreation of complex multicellular tissues in vitro using bioprinting approaches that enable precise placement of individual cells to experimentally test the influence of complex spatial arrangements. In parallel, mathematical models and supporting computational infrastructure are now being developed that can organize this information so that it can be used to model the behavior of complex diseased tissues, to predict responses to multiple perturbations, and to identify key interactions that can be manipulated to return precancerous tissues to more normal function. In this project, we will leverage these recently developed analytical tools and computational models to develop dynamic, multidrug treatments that control intercellular interactions in ways that predictively change the form and function of precancerous tissues to halt disease progression at the earliest stages. We will start with a well-defined laboratory “tissue” comprised of prioritized cell types known to be important in early-stage tumorigenesis, but will develop the concepts and tools in ways that can be scaled to describe and manage the more complex precancerous tissues that we eventually expect to be able to control. This proposal has the potential to broadly impact patient outcomes by identifying novel, minimally toxic therapeutic strategies designed to treat cancer at the earliest stages, when therapies are most likely to lead to curative responses.