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RUNX1 Modulates TGF-β1-Induced Myofibroblast Differentiation in Human Prostate-Derived Mesenchymal Stem Cells Woosook Kim, David Barron, Rebeca San Martin, and David Rowley Baylor College of Medicine, Houston, TX Reactive stroma in prostate cancer is typified by the co-evolution of myofibroblasts. This reactive stroma is associated with most human carcinoma and more reactive stroma is predictive of aggressive disease progression. TGFβ1 is a key factor in regulating reactive stroma biology. However, the origin of myofibroblasts and the mechanisms of how TGF-β1 recruits, activates, and induces their differentiation are essentially unknown. We have identified mesenchymal stem cells from normal human prostate gland and evaluated their biology in a novel 3D co-culture system. Human prostate-derived mesenchymal stem cells (hpMSCs) were CD44+CD90+ and exhibited multilineage differentiation potential. When co-cultured with LNCaP prostate cancer cells or co-inoculated in nude mice, self-organizing organoids formed with a core of stromal cells and a peripheral mantel of LNCaP cells. To investigate the role of TGF-β1, hpMSCs were co-cultured with LNCaP cells engineered to overexpress active TGF-β1. LNCaP cells overexpressing TGF-β1 induced hpMSC differentiation to prototypical reactive stroma myofibroblasts and expression of TGF-β1 in LNCaP cells led to differential gene expression in hpMSCs. Of those gene expression profiles, RUNX1 was identified as a key transcription factor in hpMSC that mediates TGF-β1-induced myofibroblast differentiation. Knockdown of RUNX1 in hpMSC significantly promoted differentiation to myofibroblasts. Conversely, overexpression of RUNX1 inhibited a myofibroblast gene expression signature. Furthermore, RUNX1 repression in hpMSC completely halted cellular proliferation by inducing G2/M phase cell cycle arrest. Together, our data show that reactive stroma in prostate cancer initiates from activation and differentiation of CD44+CD90+ endogenous hpMSCs. Moreover, our data indicate that RUNX1 is required for transit-amplifying cell proliferation to gain a critical mass of myofibroblasts that results in a tumor-promoting reactive stroma. Therefore, RUNX1 functions as a key modulator of reactive stroma formation in cancer by playing a permissive role in cell proliferation.