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The Msi1-mTOR pathway drives the pathogenesis of mammary and extramammary Paget’s disease

Authors :
Christian F. Guerrero-Juarez
Xiaole Sheng
Guang-Biao Zhou
Yiqiang Zhao
Jiuzhi Xu
Ran Zhao
Bogi Andersen
Xueyun Bi
Fazheng Ren
Yuhua Tian
Zhaoxia Ying
Cong Lv
Yunlu Zhu
Sujuan Du
Qing Nie
Xianghui Ma
Yongli Song
Jianwei Shuai
Lina Bu
Hong-Duo Chen
Shi-Jun Shan
Ruiqi Liu
Lixiang Xue
Maksim V. Plikus
Yeqiang Liu
Min Deng
Yichen Tang
Xing Dai
Christopher J. Lengner
Zhongjian Chen
Zhengquan Yu
Source :
Cell Research
Publication Year :
2020
Publisher :
Springer Science and Business Media LLC, 2020.

Abstract

Mammary and extramammary Paget's Diseases (PD) are a malignant skin cancer characterized by the appearance of Paget cells. Although easily diagnosed, its pathogenesis remains unknown. Here, single-cell RNA-sequencing identified distinct cellular states, novel biomarkers, and signaling pathways - including mTOR, associated with extramammary PD. Interestingly, we identified MSI1 ectopic overexpression in basal epithelial cells of human PD skin, and show that Msi1 overexpression in the epidermal basal layer of mice phenocopies human PD at histopathological, single-cell and molecular levels. Using this mouse model, we identified novel biomarkers of Paget-like cells that translated to human Paget cells. Furthermore, single-cell trajectory, RNA velocity and lineage-tracing analyses revealed a putative keratinocyte-to-Paget-like cell conversion, supporting the in situ transformation theory of disease pathogenesis. Mechanistically, the Msi1-mTOR pathway drives keratinocyte-Paget-like cell conversion, and suppression of mTOR signaling with Rapamycin significantly rescued the Paget-like phenotype in Msi1-overexpressing transgenic mice. Topical Rapamycin treatment improved extramammary PD-associated symptoms in humans, suggesting mTOR inhibition as a novel therapeutic treatment in PD.

Details

ISSN :
17487838 and 10010602
Volume :
30
Database :
OpenAIRE
Journal :
Cell Research
Accession number :
edsair.doi.dedup.....6261562f960dd160830d142877a8f257