Li Zhijie, Koch Kelsey E, Thompson Dakota T, Van der Heide Dana M, Chang Jeremy, Franke Christopher M, Suraju Mohammed O, Beck Anna C, Lorenzen Allison W, White Jeffrey R, Bartschat Nicholas I, Kulak Mikhail V, Meyerholz David K, Kenny Colin, Weigel Ronald J
Department of Surgery, University of Iowa, Iowa City, IA 52242, USA.
Department of Pathology, University of Iowa, Iowa City, IA 52242, USA.
Dev Cell. 2025 Apr 25. doi: 10.1016/j.devcel.2025.04.005.
The small ubiquitin-like modifier (SUMO) pathway is required for maintenance of cancer stem cells/tumor-initiating cells (CSCs/TICs), which drive tumorigenesis when transplanted into immunocompromised mice. We found that inhibition of the SUMO pathway blocked Neu-mediated mammary oncogenesis and inhibited the function of CSCs/TICs without effects on normal mammary stem cells. Transcriptomic analysis implicated SUMO-conjugated Etv1 as being critical for oncogenesis. After SUMO pathway inhibition, a SUMO-mimetic Etv1 protein, created by a fusion with SUMO1 or SUMO2, established a stem-like cell capable of tumorigenesis, whereas a SUMO-resistant Etv1 protein established a proliferative, non-tumorigenic cell. In mixing experiments, stem-like cells induced tumorigenesis by non-stem cells. We conclude that SUMO-conjugated Etv1 is necessary to maintain the CSC/TIC phenotype and that crosstalk between stem and non-stem cells is crucial for tumorigenesis. The findings demonstrate dynamic interactions between heterogeneous cell types to drive tumorigenesis, which has implications for future cancer therapeutic development.
小泛素样修饰物（SUMO）途径是维持癌症干细胞/肿瘤起始细胞（CSCs/TICs）所必需的，当将这些细胞移植到免疫缺陷小鼠体内时会驱动肿瘤发生。我们发现抑制SUMO途径可阻断Neu介导的乳腺肿瘤发生，并抑制CSCs/TICs的功能，而对正常乳腺干细胞无影响。转录组分析表明SUMO共轭的Etv1对肿瘤发生至关重要。SUMO途径抑制后，通过与SUMO1或SUMO2融合产生的SUMO模拟Etv1蛋白可形成具有肿瘤发生能力的干细胞样细胞，而SUMO抗性Etv1蛋白则形成增殖性、非致瘤性细胞。在混合实验中，干细胞样细胞可诱导非干细胞发生肿瘤。我们得出结论，SUMO共轭的Etv1对于维持CSC/TIC表型是必要的，并且干细胞与非干细胞之间的相互作用对于肿瘤发生至关重要。这些发现证明了异质性细胞类型之间的动态相互作用以驱动肿瘤发生，这对未来癌症治疗的发展具有启示意义。
