Heterotypic competition between cancer cells and hepatocytes generates heterogeneous context-dependent phenotypes

Competitive interactions between tumor cells and surrounding healthy cells are constantly present during the progression of a solid tumor, and their outcome has been proposed to affect the clinical behavior. Previous studies have described various mechanistic and molecular aspects that characterize this process, overall indicating that cancer cells behave as supercompetitors, which eliminate neighboring healthy cells to gain vital space for growth and infiltration of the tissue. Nevertheless, there is a lack of systematic characterization of these competitive interactions, particularly in the context of cancer in mammals. Furthermore, previous studies in the field of cell competition have primarily focused on homotypic cell competition, involving different clones of the same cell or cells deriving from the same tissue. Data are scarce regarding heterotypic cell competition between two unrelated cell types, which is particularly critical for the understanding of metastatic tumors. In this research, we study cell competition in the context of liver metastases, providing a broad characterization of this process in different relevant scenarios, including cells growing in vitro in 2D and 3D, and in vivo. Results show that in vitro, only a subset of cancer cell lines are coherently strong or moderate competitors against hepatocytes, while the remaining demonstrate poor competitiveness. The competitive proficiency can vary depending on the experimental growth system that is employed, and often predicts the phenotype of liver metastases in terms of aggressiveness and morphology. Finally, our data point towards an involvement of mechanical competition in determining the supercompetitor trait of cancer cells. Altogether, our research provides the first comprehensive characterization of heterotypic cell competition, and indicates that cancer cells possess heterogeneous competitive proficiency towards hepatocytes which can be affected by the growth conditions.