Hematopoietic transcription factor RUNX1 is essential for promoting macrophage-myofibroblast transition in non-small-cell lung carcinoma

Abstract

Macrophage-myofibroblast transition (MMT) is a newly discovered pathway for mass production of pro-tumoral cancer-associated fibroblasts (CAFs) in non-small cell lung carcinoma (NSCLC) in a TGF-beta 1/Smad3 dependent manner. Better understanding its regulatory signaling in tumor microenvironment (TME) may identify druggable target for the development of precision medicine. Here, by dissecting the transcriptome dynamics of tumor-associated macrophage at single-cell resolution, a crucial role of a hematopoietic transcription factor Runx1 in MMT formation is revealed. Surprisingly, integrative bioinformatic analysis uncovers Runx1 as a key regulator in the downstream of MMT-specific TGF-beta 1/Smad3 signaling. Stromal Runx1 level positively correlates with the MMT-derived CAF abundance and mortality in NSCLC patients. Mechanistically, macrophage-specific Runx1 promotes the transcription of genes related to CAF signatures in MMT cells at genomic level. Importantly, macrophage-specific genetic deletion and systemic pharmacological inhibition of TGF-beta 1/Smad3/Runx1 signaling effectively prevent MMT-driven CAF and tumor formation in vitro and in vivo, representing a potential therapeutic target for clinical NSCLC. Macrophage-myofibroblast transition (MMT) is an important source of cancer-associated fibroblasts (CAFs) in non-small cell lung carcinoma (NSCLC). Here, the hematopoietic transcription factor Runx1 is discovered as a key regulator of MMT in cancer patients. Macrophage-specific and systemic inhibition of Runx1 effectively blocks MMT-driven tumor formation in vivo, representing a druggable therapeutic target to eliminate tumor-promoting CAFs in NSCLC patients.