Collapse of Intra-Tumor Cooperation Induced by Engineered Defector Cells.

Marco Archetti

doi:10.3390/cancers13153674

Abstract

Simple SummaryUsing 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.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.

Highlights

Introduction published maps and institutional affilCancer treatment failure is often caused by the evolution of resistant clones within a tumor due to the clonal selection of mutant cells that evade therapy
Non-producer cells can spread in a population of producer cells and induce the collapse of cooperation; The collapse of cooperation requires a high cost/benefit ratio of growth factor production; The collapse of cooperation impairs proliferation if the benefit conferred by the growth factor is high enough; Improving the growing conditions of the cell culture can induce the collapse of cooperation; The collapse of cooperation, if it occurs, is stable and self-promoting
The first issue is that in some cases, the WT clone does not go extinct, remaining instead at a stable mixed equilibrium with the KO clone. This is predicted by evolutionary game theory for systems in which the benefit of the growth factor is a nonlinear function of its concentration [20,21,22,23,24,25,26], which is likely to be the case for all growth factors

Summary

Introduction

Cancer treatment failure is often caused by the evolution of resistant clones within a tumor due to the clonal selection of mutant cells that evade therapy These clones can proliferate faster than the original susceptible ones, spreading within the tumor and eventually leading to population-wide resistance. Recent less conventional treatment strategies have applied evolutionary principles to inhibit the emergence of treatment-resistant populations by the appropriately timed withdrawal of treatment [9,10,11]. The logic of this “adaptive therapy” is to harness iations

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