DMS/NIGMS 2: Regulation of Cellular Stemness during the Epithelial-Mesenchymal Transition (EMT)

This research will involve a joint theoretical/experimental approach to address cell-fate trajectories that occur during induction of the epithelial-mesenchymal transition (EMT). The EMT transition was originally discovered in the context of developmental biology and refers to the fact that cells can dramatically change their phenotypic behavior from a sedentary, strongly-adherent lifestyle (“epithelial”) to one characterized by motility and weaker cell-cell coupling (“mesenchymal”). This transition was later shown to be directly relevant for the onset of metastatic spread of primary tumors. Recent efforts have indicated that epithelial cells can either undergo direct reprogramming to mesenchymal states or alternatively become more stem-like and exhibit intermediate, hybrid E/M properties. These latter states appear to be the most effective at initiating new tumors and hence the most dangerous. Based on the investigators’ preliminary investigations, state-of-the-art single cell measurement technology will be used together with advanced mathematical modeling frameworks to understand how cells choose specific fates and to quantitatively unravel the genetic and epigenetic dynamics that leads these cells along their particular trajectories. The investigators will develop new mathematical concepts such as the role of frustration in cell fate networks; here frustration refers to the incompatibility of various genetic interactions and understanding how it enables the aforementioned intermediate states can help develop ideas to interdict their effects. The investigators will also study the role of “epigenetic” modifiers, chemical modifications of proteins that help package the DNA that directly affect how easy it is to switch between different phenotypes. The project also will have possible spillovers into translational applications. Technically, the projected research will consist of several interwoven areas coupling mathematics to biology. The investigators will take full advantage of modern single-cell technology to create datasets that will be used to quantitatively determine the step-by-step progress of EMT and concomitant stemness properties of cells, measuring both transcriptional profiles and features of the chromatin-dependent epigenetics. These data will help formulate new types of dynamical models, both deterministic and stochastic, coupling transcriptional regulation to a dynamically modifiable underling epigenetic landscape. These models will be used to understand the role of frustration, i.e. unsatisfied regulatory interactions in a given phenotypic state of the network, in the enabling of intermediate states with enhanced plasticity; this understanding could have direct translational relevance, as plasticity has been implicate in tumor initiation and in tumor therapy resistance. The data will also help develop and better understand the validity of advanced data analysis techniques such as the concept of optimal transport which allows for trajectory inference. This powerful idea requires the use of cost functions to relate data at different timepoints and the investigators will use both synthetic and actual data to explore the idea that incomplete mechanistic models can be used to create better such cost functions. All told, this research will greatly improve the understanding of cell-fate transitions and how they depend on the detailed molecular level underpinnings of genetic circuits governing transcriptional and translational processes and the epigenetic landscape to which these circuits are reciprocally coupled. 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.