Cancer cell – fibroblast crosstalk signature promotes macrophage recruitment via HB-EGF and stromal EGFR/MEK signalling

Abstract

SummaryInteractions 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 adopt a distinct approach that exploits patterns of gene expression indicative of signalling between stromal fibroblasts and cancer cells, and demonstrate the prognostic significance of these gene signatures in multiple and independent squamous cell carcinoma cohorts. We discover that HB-EGF in cancer cells and EGFR in cancer associated fibroblasts represent a hub of tumor – stroma crosstalk through MAPK signalling and AP-1 transcription factor. We find divergent consequences for pathway activation in cancer cells compared to stromal fibroblasts that favours macrophages recruitment. Together these analyses demonstrate the utility of this new approach to interrogating the extent and consequences of TME crosstalk. By focusing on the transcriptional consequences of cancer cell-fibroblast interactions we derive prognostic signatures and uncover molecular mechanisms promoting fibroblast to macrophage communication.