Physical Models for Cancer Cells with Links to Alterations in Genome Organization

University Of Texas At Austin, Austin TX

Investigators

Abstract

Cancer is an evolutionary disease caused by steady accumulation of sequential somatic mutations. By gaining fitness advantage, cancer cells undergo rapid growth. The overarching goals of this award are to use theory and computations to provide quantitative predictions for collective motions of mixtures of cancer and normal cells and link them to changes in genome organization and dynamics. To accomplish the goals, the Principal Investigator (PI) will create physical models to elucidate the principles governing collective cell dynamics in mixtures of two cell types. The PI will also investigate the differences in the three-dimensional organization and dynamics of chromosomes between normal and cancer cells. The two major problems that the PI wishes to solve, using physics-based ideas, emerge from the following observations. First, it is unclear how the generation of a single cancer cell interacts with normal cells, and eventually spreads without control. Second, what are the differences between movements of normal and cancer cells as they move through constrictions that arise through cell jamming? The proposed problems were generated by surveying recent experiments have generated questions that can be quantitatively addressed using theoretical and computational methods. To address how cancer cells invade the space of normal cells, in this award, the investigators will develop methods to solve the organization and dynamics when cancer cells are mixed with normal cells. Indeed, in all aspects of tissue formation, ranging from development to breakdown of their structures during cancer and other diseases, the description of how multiple cell types organize themselves is a difficult but an important issue. In this award, the Investigators will develop novel models to simulate the structures and dynamics of mixtures of cells as a function of cell-cell adhesion, cell-matrix interactions, and cell division, and apoptosis. The second goal is to study the effect of cell movement through constrictions on chromosomes in normal and cancer cells. As cells move, their motions are constricted through cell jamming, driven by self-crowding of cells and confinement, which profoundly affect chromatin structures, possibly resulting in altered gene expression. Most recent experiments have given glimpses of the differences in the chromosome organization between normal and cancer cells. The ability of a primary tumor to migrate to distant parts involves a cascade of steps in the invasion of the cancer cells into heathy tissues. During migration, cancer cells have to, at least occasionally, squeeze through constrictions in the extra cellular matrix surrounding the cells. The sizes of the constrictions could be smaller than the nucleus size, which potentially deforms the genome in the cells. The natural questions that need to be answered by this award are: Does the deformation of the nucleus alter the organization of the chromosomes? What insights can one gain by using theoretical methods to quantitatively understand these experiments? Answering these questions requires development of models that go roughly from the molecular scale to tissue level. The broader impacts of this award will include the development of curated software, which will be made publicly available. This award will also contribute to the training of students and postdoctoral fellows in interdisciplinary fields. 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.