Department of Medical Oncology of The Eastern Hospital, The First Affiliated Hospital, Sun Yat-Sen University, No.58, Zhong Shan Er Lu, Guangzhou, 510080, China.
Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Med Oncol. 2022 Oct 12;39(12):254. doi: 10.1007/s12032-022-01859-w.
Small cell lung cancer (SCLC) is one of the most malignant types of lung cancer. Cancer stem cell (CSC) and tumor immune evasion are critical for the development of SCLC. We previously reported that NDR1 enhances breast CSC properties. NDR1 might also have a role in the regulation of immune responses. In the current study, we explore the function of NDR1 in the control of CSC properties and evasion of phagocytosis in SCLC. We find that NDR1 enhances the enrichment of the ALDEFLUOR and CD133 population, and promotes sphere formation in SCLC cells. Additionally, NDR1 upregulates CD47 expression to enhance evasion of phagocytosis in SCLC. Furthermore, the effects of NDR1 enhanced CD47 expression and evasion of phagocytosis are more prominent in CSC than in non-CSC. Importantly, NDR1 promotes ASCL1 expression to enhance NDR1-promoted CSC properties and evasion of phagocytosis in SCLC cells. Mechanically, NDR1 enhances protein stability and the nuclear location of ASCL1 to activate the transcription of CD47 in SCLC. Finally, CD47-blocking antibody can be used to target NDR1 enhanced CSC properties and evasion of phagocytosis by suppressing EGFR activation in SCLC. In summary, our data indicate that NDR1 could be a critical factor for modulating CSC properties and phagocytosis in SCLC.
小细胞肺癌(SCLC)是最恶性的肺癌类型之一。癌症干细胞(CSC)和肿瘤免疫逃逸对于 SCLC 的发展至关重要。我们之前报道过,NDR1 增强了乳腺癌 CSC 的特性。NDR1 可能在免疫反应的调节中也有作用。在本研究中,我们探讨了 NDR1 在控制 SCLC 中 CSC 特性和吞噬逃避中的作用。我们发现 NDR1 增强了 ALDEFLUOR 和 CD133 群体的富集,并促进了 SCLC 细胞的球体形成。此外,NDR1 上调 CD47 的表达,以增强 SCLC 中的吞噬逃避。此外,在 CSC 中,NDR1 增强 CD47 表达和吞噬逃避的作用比非 CSC 更为显著。重要的是,NDR1 促进 ASCL1 的表达,以增强 NDR1 促进的 SCLC 细胞中的 CSC 特性和吞噬逃避。从机制上讲,NDR1 通过增强 ASCL1 的蛋白稳定性和核定位来激活 SCLC 中 CD47 的转录。最后,CD47 阻断抗体可用于通过抑制 SCLC 中 EGFR 的激活来靶向 NDR1 增强的 CSC 特性和吞噬逃避。总之,我们的数据表明,NDR1 可能是调节 SCLC 中 CSC 特性和吞噬逃避的关键因素。