Secreted factors from M1 macrophages drive prostate cancer stem cell plasticity by upregulating NANOG, SOX2 and CD44 through NFκB signaling [LNCaP-C42B]

The inflammatory tumor microenvironment (TME) is a key driver of tumor-promoting pro-cesses. Tumor-associated macrophages are one of the main immune cell types in the TME and their increased density is related to poor prognosis in prostate cancer. Here, we investigated the influence of pro-inflammatory (M1) and immunosuppressive (M2) macrophages on pros-tate cancer lineage plasticity. Our findings reveal that M1 macrophage secreted factors up-regulate genes related to stemness while downregulating genes associated with androgen re-sponse in prostate cancer cells. The expression of cancer stem cell plasticity markers NANOG, KLF4, SOX2, OCT4 and CD44 was stimulated by the secreted factors from M1 macrophages. Moreover, AR and its target gene KLK3 were observed to be suppressed in LNCaP cells treated with secreted factors from M1 macrophages. Inhibition of NFκB signaling using the IKK16 inhibitor resulted in downregulation of NANOG, SOX2 and CD44 and cancer stem cell plasticity. 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 NFκB signaling pathway.