Cancer cell – fibroblast crosstalk via HB-EGF/EGFR/MEK signaling promotes macrophage recruitment in squamous cell carcinoma

Summary Interactions between cells in the tumor microenvironment (TME) shape cancer progression and patient outcomes. To gain new insights into how the TME influences cancer outcomes, we derive gene expression signatures indicative of signaling between stromal fibroblasts and cancer cells, and demonstrate their prognostic significance in multiple and independent squamous cell carcinoma cohorts. By leveraging information within the signatures, we discover that the HB-EGF/EGFR/MEK axis represents a hub of tumor – stroma crosstalk, promoting the expression of CSF2 and LIF and favoring the recruitment of macrophages. Together these analyses demonstrate the utility of our approach for interrogating the extent and consequences of TME crosstalk.