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作者

Yan Guo Xiaoqin Lu Yao Chen Geoff Clark John Trent Miriam Cuatrecasas Douglas Emery Zhao-Hui Song Julia Chariker Eric Rouchka Antonio Postigo Yongqing Liu Douglas C. Dean

作者单位

²Department of Hematology, The First Affiliated Hospital of Shandong First Medical University, Jinan 250014, China ⁵Department of Pathology, Centro de Diagnóstico Biomédico (CDB) Hospital Clínic, University of Barcelona, 08036 Barcelona, Spain ³Department of Ophthalmology, Xiangya Hospital of Central South University, Changsha, China ¹Department of Medicine, Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY 40202, USA ⁷Group of Transcriptional Regulation of Gene Expression, IDIBAPS and University of Barcelona School of Medicine, 08036 Barcelona, Spain ⁶Department of Computer Engineering and Computer Science, Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY 40202, USA ⁸ICREA, 08010 Barcelona, Spain ⁹Lead contact ⁴Department of Pharmacology, Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY 40202, USA

刊名

Cell Reports

年份

2022

卷号

Vol.41 No.1

页码

111452

ISSN

2211-1247

关键词

lung cancer Zeb1 Yap1 invasion Rassf1a Id2 RhoA EMT actin cytoskeleton lung epithelial differentiation

摘要

Epithelial-mesenchymal transition facilitates cancer invasion and is initiated by mesenchyme-driving transcription factors and actin cytoskeletal assembly. We show a cytoplasmic-to-nuclear transport gradient of the EMT transcription factor Zeb1 toward sites of invasion in lung adenocarcinoma , driven by the EMT inducer Tgfb, which is expressed in M2 polarized macrophages. We show that Zeb1 binds free actin monomers and RhoA in the cytoplasm to inhibit actin polymerization, blocking cell migrati...更多

Epithelial-mesenchymal transition facilitates cancer invasion and is initiated by mesenchyme-driving transcription factors and actin cytoskeletal assembly. We show a cytoplasmic-to-nuclear transport gradient of the EMT transcription factor Zeb1 toward sites of invasion in lung adenocarcinoma , driven by the EMT inducer Tgfb, which is expressed in M2 polarized macrophages. We show that Zeb1 binds free actin monomers and RhoA in the cytoplasm to inhibit actin polymerization, blocking cell migration and Yap1 nuclear transport. Tgfb causes turnover of the scaffold protein Rassf1a, which targets RhoA. Release of this RhoA inhibition in response to Tgfb overcomes Zeb1’s block of cytoskeleton assembly and frees it for nuclear transport. A ZEB1 nuclear transport signature highlights EMT progression, identifies dedifferentiated invasive/metastatic human LUADs, and predicts survival. Blocking Zeb1 nuclear transport with a small molecule identified in this study inhibits cytoskeleton assembly, cell migration, Yap1 nuclear transport, EMT, and precancerous-to-malignant transition.收起

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