Collapse of Intra-Tumor Cooperation Induced by Engineered Defector Cells

Abstract

Simple Summary Using experiments in vitro and a mathematical model, I show that genetically modified cancer cells in which the gene for an essential growth factor is knocked out can spread in a population of cells that produce that growth factor, leading to an overall reduction in proliferation—a proof of principle for a potential treatment that harnesses clonal selection by impairing intra-tumor cooperation. Abstract Anti-cancer therapies promote clonal selection of resistant cells that evade treatment. Effective therapy must be stable against the evolution of resistance. A potential strategy based on concepts from evolutionary game theory is to impair intra-tumor cooperation using genetically modified cells in which genes coding for essential growth factors have been knocked out. Such engineered cells would spread by clonal selection, driving the collapse of intra-tumor cooperation and a consequent reduction in tumor growth. Here, I test this idea in vitro in four cancer types (neuroendocrine pancreatic cancer, mesothelioma, lung adenocarcinoma and multiple myeloma). A reduction, or even complete eradication, of the producer clone and the consequent reduction in cell proliferation, is achieved in some but not all cases by introducing a small fraction of non-producer cells in the population. I show that the collapse of intra-tumor cooperation depends on the cost/benefit ratio of growth factor production. When stable cooperation among producer and non-producer cells occurs, its collapse can be induced by increasing the number of growth factors available to the cells. Considerations on nonlinear dynamics in the framework of evolutionary game theory explain this as the result of perturbation of the equilibrium of a system that resembles a public goods game, in which the production of growth factors is a cooperative phenotype. Inducing collapse of intra-tumor cooperation by engineering cancer cells will require the identification of growth factors that are essential for the tumor and that have a high cost of production for the cell.