High-order interaction modeling of tumor-microenvironment crosstalk for tumor growth

Signaling interactions between cancer cells and nonmalignant cells in the tumor microenvironment (TME) are believed to influence tumor progression and drug resistance. However, the genomic machineries mediating such an influence remain elusive, making it difficult to determine therapeutic targets on the tumor and its microenvironment. Here, we argue that a computational model, derived from the integration of evolutionary game theory and ecosystem theory through allometric scaling law, can chart the genomic atlas of high-order interaction networks involving tumor cells, TME, and tumor mass. We assess the application of this model to identify the causal influence of gene-induced tumor-TME crosstalk on tumor growth. The findings demonstrate that cooperation and competition between tumor cells and their infiltrating microenvironment promote or inhibit tumor growth in diverse ways. We identify specific genes that govern this promotion or inhibition, which can be used as genetic targets to alter tumor growth. This model opens up a new avenue to precisely infer the genomic underpinnings of tumor-TME interactions and their impact on tumor progression from any omics data.