Xu Tong, Zhang Wanli, Gong Shaobo, Jiang Bo, Fu Zhiyi, Song Feifeng, Zhang Yiwen, Huang Ping
Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, China.
Zhejiang Provincial Clinical Research Center for Malignant Tumor, Hangzhou, China.
FASEB J. 2025 Apr 15;39(7):e70494. doi: 10.1096/fj.202402855R.
Lymph node metastasis (LNM) holds substantial implications for the recurrence and survival of cancer patients, but the intricate regulatory mechanisms underlying LNM remain poorly understood. MTOGB was dominantly increased in LNM of pan-cancer, significantly activated in epithelial cells and enriched in LNM. Subsequently, we identified a specific epithelial cell subpopulation, EC4, located at the terminal of the LNM differentiation trajectory Lineage2. By intersecting differentially expressed genes in cluster 2, EC4 and Lineage2, we identified six crucial genes. Notably, the expression of Steroid 5α-reductase 3 (SRD5A3) increased with the progression of LNM stages. Knockdown of SRD5A3 effectively suppressed the MTOGB, blocking metastasis in both cell and animal models. Nilotinib was screened as a candidate inhibitor of SRD5A3 and was confirmed to remarkably decrease cancer cell metastasis. SOX4 was identified as a potential transcription factor of SRD5A3, modulated by a dramatic increase in cell communication of SPP1 macrophages in the immune microenvironment. The supernatant from SPP1 macrophage significantly enhanced the expression of SOX4/SRD5A3 and the metastatic ability of cancer cells, and this effect was reversed by the deletion of SPP1. Collectively, our findings illuminate the SPP1-SRD5A3 signaling as the crucial driver in LNM and suggest that its blockade could be a promising option for overcoming LNM.
淋巴结转移（LNM）对癌症患者的复发和生存具有重大影响，但LNM背后复杂的调控机制仍知之甚少。MTOGB在泛癌的LNM中显著增加，在上皮细胞中显著激活，并在LNM中富集。随后，我们鉴定出一个特定的上皮细胞亚群EC4，位于LNM分化轨迹谱系2的末端。通过交叉分析簇2、EC4和谱系2中的差异表达基因，我们鉴定出六个关键基因。值得注意的是，类固醇5α-还原酶3（SRD5A3）的表达随着LNM阶段的进展而增加。敲低SRD5A3可有效抑制MTOGB，在细胞和动物模型中均阻断转移。筛选出尼罗替尼作为SRD5A3的候选抑制剂，并证实其可显著降低癌细胞转移。SOX4被鉴定为SRD5A3的潜在转录因子，受免疫微环境中SPP1巨噬细胞细胞通讯显著增加的调节。SPP1巨噬细胞的上清液显著增强了SOX4/SRD5A3的表达和癌细胞的转移能力，而删除SPP1可逆转这种效应。总的来说，我们的研究结果阐明了SPP1-SRD5A3信号通路是LNM的关键驱动因素，并表明阻断该信号通路可能是克服LNM的一个有前景的选择。
