Cancer cell – Fibroblast crosstalk via HB-EGF, EGFR, and MAPK signaling promotes the expression of macrophage chemo-attractants in squamous cell carcinoma

Interactions between cells in the tumor microenvironment (TME) shape cancer progression and patient prognosis. To gain 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/MAPK 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. [Display omitted] •Cancer cell – fibroblast crosstalk signatures are associated with worse survival•Crosstalk is activated via direct contact through HB-EGF/EGFR/MEK/AP-1 axis•Tumor HB-EGF and stromal EGFR regulate GM-CSF and LIF expression•High cancer cell – fibroblast crosstalk correlates with a macrophage-rich environment Microenvironment; Cancer; Transcriptomics