Aberrant epithelial cell interaction promotes esophageal squamous-cell carcinoma development and progression.

Chen L, Zhu S, Liu T, Zhao X, Xiang T, Hu X, Wu C, Lin D

Signal Transduct Target Ther 2023

1. Signal Transduct Target Ther. 2023 Dec 15;8(1):453. doi: 10.1038/s41392-023-01710-2. Aberrant epithelial cell interaction promotes esophageal squamous-cell carcinoma development and progression. Chen L(#)(1), Zhu S(#)(1), Liu T(1), Zhao X(1), Xiang T(1), Hu X(1), Wu C(2)(3)(4)(5), Lin D(6)(7)(8)(9). Author information: (1)Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. (2)Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. chenwu@cicams.ac.cn. (3)Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. chenwu@cicams.ac.cn. (4)Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, China. chenwu@cicams.ac.cn. (5)CAMS Oxford Institute, Chinese Academy of Medical Sciences, Beijing, 100006, China. chenwu@cicams.ac.cn. (6)Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. lindx@cicams.ac.cn. (7)Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. lindx@cicams.ac.cn. (8)Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, China. lindx@cicams.ac.cn. (9)Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, 510060, China. lindx@cicams.ac.cn. (#)Contributed equally Epithelial-mesenchymal transition (EMT) and proliferation play important roles in epithelial cancer formation and progression, but what molecules and how they trigger EMT is largely unknown. Here we performed spatial transcriptomic and functional analyses on samples of multistage esophageal squamous-cell carcinoma (ESCC) from mice and humans to decipher these critical issues. By investigating spatiotemporal gene expression patterns and cell-cell interactions, we demonstrated that the aberrant epithelial cell interaction via EFNB1-EPHB4 triggers EMT and cell cycle mediated by downstream SRC/ERK/AKT signaling. The aberrant epithelial cell interaction occurs within the basal layer at early precancerous lesions, which expands to the whole epithelial layer and strengthens along the cancer development and progression. Functional analysis revealed that the aberrant EFNB1-EPHB4 interaction is caused by overexpressed ΔNP63 due to TP53 mutation, the culprit in human ESCC tumorigenesis. Our results shed new light on the role of TP53-TP63/ΔNP63-EFNB1-EPHB4 axis in EMT and cell proliferation in epithelial cancer formation. © 2023. The Author(s). DOI: 10.1038/s41392-023-01710-2 PMCID: PMC10721848 PMID: 38097539 [Indexed for MEDLINE] Conflict of interest statement: The authors declare no competing interests.