Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA.
Olympus Veran Technologies, St. Louis, MO, USA.
Nat Commun. 2023 Apr 13;14(1):2110. doi: 10.1038/s41467-023-37914-x.
Activation of HER2/ErbB2 coincides with escape from ductal carcinoma in situ (DCIS) premalignancy and disrupts 3D organization of cultured breast-epithelial spheroids. The 3D phenotype is infrequent, however, and mechanisms for its incomplete penetrance have been elusive. Using inducible HER2/ErbB2-EGFR/ErbB1 heterodimers, we match phenotype penetrance to the frequency of co-occurring transcriptomic changes and uncover a reconfiguration in the karyopherin network regulating ErbB nucleocytoplasmic transport. Induction of the exportin CSE1L inhibits nuclear accumulation of ErbBs, whereas nuclear ErbBs silence the importin KPNA1 by inducing miR-205. When these negative feedbacks are incorporated into a validated systems model of nucleocytoplasmic transport, steady-state localization of ErbB cargo becomes ultrasensitive to initial CSE1L abundance. Erbb2-driven carcinomas with Cse1l deficiency outgrow less irregularly from mammary ducts, and NLS-attenuating mutants or variants of HER2 favor escape in 3D culture. We conclude here that adaptive nucleocytoplasmic relocalization of HER2 creates a systems-level molecular switch at the premalignant-to-malignant transition.
HER2/ErbB2 的激活与导管原位癌 (DCIS) 前恶性肿瘤的逃逸同时发生，并破坏培养的乳腺上皮球体的 3D 组织。然而，这种 3D 表型并不常见，其不完全表现的机制也难以捉摸。我们使用可诱导的 HER2/ErbB2-EGFR/ErbB1 异二聚体，将表型穿透率与转录组变化的频率相匹配，并揭示了调节 ErbB 核质转运的核孔蛋白网络的重新配置。导出蛋白 CSE1L 的诱导抑制了 ErbB 的核积累，而核 ErbB 通过诱导 miR-205 沉默导入蛋白 KPNA1。当这些负反馈被纳入核质转运的验证系统模型时，ErbB 货物的稳态定位对初始 CSE1L 丰度变得超敏感。Cse1l 缺乏的 Erbb2 驱动的癌瘤从乳腺导管中不规则生长的情况较少，NLS 减弱的突变体或 HER2 的变体有利于在 3D 培养中逃逸。我们在这里得出的结论是，HER2 的适应性核质再定位在癌前到恶性转化的过渡中创建了一个系统级的分子开关。
