IL6/JAK/STAT3-mediated crosstalk between cancer associated fibroblasts and epithelial cells promotes lineage plasticity and prostate cancer progression [scATAC-seq]
Prostate cancer is a heterogeneous disease with a slow progression and a highly variable clinical outcome. The tumor suppressor gene TP53 is frequently mutated in prostate cancer and predictive of an early metastatic dissemination and unfavorable patient outcome. The progression of solid tumors to metastatic cancer is often associated with increased cell plasticity, but the mechanism underlying TP53-loss induced disease aggressiveness is unknown. Here we show that Trp53 deficiency in Pten-null prostatic epithelial cells does not impact the early proliferation of Pten-null epithelial cells and prostatic intraepithelial neoplasia formation, nor growth arrest and senescence entry at later time. Moreover, we demonstrate that it induces epithelial cell plasticity by stimulating IL6 production in cancer-associated fibroblasts, that in turn enhances Jak/Stat signaling in epithelial cells and promotes metastatic dissemination. Thus, TP53 restrains prostate cancer progression by preventing a pro-tumorigenic crosstalk between PTEN-deficient prostatic epithelial cells and the tumor microenvironment. Overall design: NOT PROVIDED; REQUESTED