STAT3 target genes encoding for secreted proteins mediate the cross-talk between cancer-associated fibroblasts and breast cancer cells

Triple-negative breast cancers (TNBCs) are the most aggressive mammary neoplasms, for which targeted therapies are lacking. An alternative could be the interference with the cross-talk established between the tumour and its microenvironment (TME) and in particular cancer-associated fibroblasts (CAFs), renowned to strongly support tumour maintenance and progression. TNBC cells consistently display constitutive activation of the oncogenic transcription factor Signal Transducer and Activator of Transcription 3 (STAT3). STAT3 promotes the transcription, among others, of the Interleukin-6 (IL-6) cytokine, which can exert both autocrine and paracrine activities. Once secreted, IL-6 can indeed act both on cells of the tumour and of the TME, leading to the activation of STAT3 that in turn promotes IL-6 production, in a feed-forward loop that supports tumour growth and metastatization. We therefore decided to assess the role exerted by STAT3 in the regulation of the cross-talk between CAFs and TNBC cells. We could demonstrate that indeed STAT3 silencing significantly blunts CAFs’ ability to enhance in vitro proliferation, migration and invasion of 4T1 TN murine breast cancer cells, as well as their ability to grow and give origin to lung metastases in vivo. We have identified a subset of STAT3-dependent CAFs-secreted factors contributing to their pro-tumourigenic functions, and validated both in vitro and in vivo the key role of four of them, IL-6, MMP13, STC1 and ANGPTL4. Finally, we demonstrated the feasibility of a therapeutic strategy based on IL-6 and MMP13 pharmacological inhibition that could be exploited in TNBC.