Secreted factors from M1 macrophages drive prostate cancer stem cell plasticity by upregulating NANOG, SOX2 and CD44 through NFκB signaling [LNCaP]

The inflammatory tumor microenvironment (TME) is a key driver of tumor-promoting processes. Tumor-associated macrophages are one of the main immune cell types in the TME and their density increases during cancer progression. Here, we investigated the influence of pro-inflammatory (M1) and immunosuppressive (M2) macrophages on prostate cancer lineage plasticity. Our findings reveal that M1 macrophage secreted factors upregulate genes related to stemness while downregulating genes associated with androgen response in LNCaP prostate cancer cells. Cancer stem cell plasticity markers NANOG, KLF4, SOX2, OCT4 and CD44 were stimulated by the secreted factors from M1 macrophages. Moreover, AR and its target gene KLK3 were observed to be suppressed in LNCaP cells treated exposed to secreted factors from M1 macrophages. Inhibition of NF-κB signaling using the IKK16 inhibitor resulted in downregulation of NANOG, SOX2 and CD44. Our study highlights that the secreted factors from M1 macrophages drive prostate cancer cell plasticity by upregulating the expression of cancer stem cell plasticity markers through NF-κB signaling pathway.