The goal of this project is to use theoretical and computational tools to decipher general principles and to quantitatively describe tumor evolution. The PI will address two problems in cancer research: (a) how the interplay of distinct types of somatic mutations impacts tumor evolution and (b) what is the mechanism of origin of tumor heterogeneity. Solutions to these problems, which are relevant to all cancers, using physics-based models and analytical tools based on concepts in glass physics will be sought. The outcome of this work will provide a quantitative and integrated picture of a few key important issues in cancer research. The results will provide a platform for analyzing clinical data, as the initial studies already demonstrate. The PI will provide training of the next generation of students and postdoctoral research fellows in the area of theoretical research on cancer in which physics concepts and quantitative methods will play an increasing role. The training of these scientists will include sustained efforts to integrate the field of glass physics into cancer research.
Two major issues will be investigated: (1) Role of beneficial passenger or mini-drivers mutations on cancer progression: According to the somatic mutation theory, cancer is caused by clonal expansion of cells due to accumulation of mutations over a life time that gives fitness advantage to tumor cells. Much of the focus has been on driver mutations as the cause of cancer, and very little attention has been paid to passenger mutation. The PI will use models that consider the interplay of driver mutations as well as deleterious and beneficial passenger mutations to obtain quantitative predictions for tumor evolution and cancer dormancy in terms of mutation rates, population size, and fitness of mutation types. (2) Physical models for Cancer Heterogeneity: There is a resurgent interest in understanding the origin of non-genetic cancer heterogeneity, although its importance in affecting cancer therapy was appreciated decades ago. Clarifying the origin of heterogeneity requires creating three dimensional models accounting for the birth and death of cells. In addition, the proposed models must include physical inter cellular forces, allowing us to quantify tumor microenvironment and its evolution with realistic dynamics. The PI will use two models that explicitly account for both spatial migration (characteristic of cells that have lost or have reduced E-cadherin expression) and adhesive forces as found in epithelial cells. The PI suggests that some of the theoretical concepts rooted in glass physics are necessary to fully understand cancer heterogeneity. The expected results will not only bridge the two fields but also provide a way to describe quantitatively the migration of cancer cells from their sites of origin to distant sites.
