A cell circuit approach to dissect fibroblast-macrophage interactions in the tumor microenvironment

The tumor microenvironment (TME) is composed of various nonmalignant cell types that interact with each other and with cancer cells, impacting all aspects of cancer biology. The TME is complex and heterogeneous, and thus simplifying systems and concepts are needed. Here we provide a tractable experimental system and powerful mathematical circuit concepts to identify the main molecular interactions that govern the composition of the TME. We focus on two major components of the TME - cancer associated fibroblasts (CAFs) and tumor associated macrophages (TAMs), define their interactions and verify our predictions in mouse and human breast cancer. We measure the population dynamics starting from many initial conditions of co-cultures of macrophages and organ-derived fibroblasts from mammary, lung, and fat, and explore the effects of cancer-conditioned medium on the circuits. We define the circuits and their inferred parameters from the data using a mathematical approach, and quantitatively compare the cell circuits in each condition. We find that while the homeostatic steady-states are similar between the organs, the cancer-conditioned medium profoundly changes the circuit. Fibroblasts in all contexts depend on autocrine secretion of growth factors whereas macrophages are more dependent on external cues, including paracrine growth factors secreted from fibroblasts and cancer cells. Transcriptional profiling reveals the molecular underpinnings of the cell circuit interactions and the primacy of the fibroblast autocrine loop. The same fibroblast growth factors are shared by the co-cultures and mouse and human breast cancer. The cell circuit approach thus provides a quantitative account of cell interactions in the cancer microenvironment.