Tissue-resident macrophages favor early lung cancer development via direct physical interactions with cancer cells

Abstract While extensive research has unraveled diverse biochemical mechanisms underlying the pro-tumorigenic activities of macrophages, the role of physical forces in early tumor development remains elusive. Here, we integrated experimental data with physical modeling to investigate the contribution of various physical forces. Monitoring the growth of KrasG12Dp53-/- (KP) lung tumor spheroids in vitro in 3 dimensions using real-time microscopy accurately reflects the role of tissue-resident macrophages, rather than monocytes, in promoting tumor growth. Based on the quantitative data, we develop a physical model of 3D spheroid growth to simulate the dynamics of proliferating cancer cells and interacting macrophages, aligning closely with experimental results. When cultured alone, KP lung cancer cells form a single aggregate that contracts over time due to limited nutrient access at the center. The introduction of macrophages promotes the nucleation of cancer cells into multiple small aggregates, which grow before fusing to form a large final aggregate. Throughout this process, macrophages facilitate nutrient access and thus favoring cell division. The theory predicts that adhesion forces between tumor cells and macrophages are essential for the observed tumorigenic effect. Among integrins potentially involved, CD11c is expressed by alveolar macrophages but not by monocytes. Blocking CD11c reduces adhesion forces, preventing spheroid nucleation by macrophages, and impairing growth. Additionally, our theory predicts the redistribution of macrophages towards the periphery of tumor aggregates over time, an evolutionary pattern that we validated in mice in vivo. These findings underscore the significant contribution of physical interactions via CD11c between tissue-resident macrophages and cancer cells in the pro-tumor effect of macrophages. Targeting this interaction could offer a new therapeutic strategy to impede early tumor development and metastasis.