Volume 30, No 10, Oct 2020

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 30 Issue 10, October 2020: 854-872

ORIGINAL ARTICLES

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

Yongli Song^1,2 , Christian F. Guerrero-Juarez^3,4 , Zhongjian Chen⁵ , Yichen Tang⁵ , Xianghui Ma¹ , Cong Lv¹ , Xueyun Bi¹ , Min Deng¹ , Lina Bu¹ , Yuhua Tian , Ruiqi Liu¹ , Ran Zhao¹ , Jiuzhi Xu¹ , Xiaole Sheng¹ , Sujuan Du¹ , Yeqiang Liu⁵ , Yunlu Zhu⁵ , Shi-jun Shan⁶ , Hong-duo Chen⁷ , Yiqiang Zhao¹ , Guangbiao Zhou⁸ , Jianwei Shuai⁹ , Fazheng Ren¹⁰ , Lixiang Xue¹¹ , Zhaoxia Ying¹² , Xing Dai¹³ , Christopher J. Lengner¹⁴ , Bogi Andersen¹⁵ , Maksim V. Plikus⁴ , Qing Nie^3,4 , Zhengquan Yu^1,*

¹State Key Laboratories for Agrobiotechnology and Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Biological Sciences, China Agricultural University, Beijing 100193, China
²College of Animal Science and Technology, Jilin Agricultural Science and Technology College, Changchun, Jilin 100132, China
³Department of Mathematics, NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, CA 92697, USA
⁴Department of Developmental and Cell Biology, Sue and Bill Gross Stem Cell Research, Center for Complex Biological Systems, University of California, Irvine, CA 92697, USA
⁵Shanghai Skin Disease Hospital, Shanghai 200443, China
⁶Department of Dermatology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361005, China
⁷Department of Dermatology, No.1 Hospital of China Medical University, Shenyang, Liaoning 110001, China
⁸State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
⁹Department of Physics and State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, Xiamen University, Xiamen, Fujian 361005, China
¹⁰Beijing Advanced Innovation Center for Food Nutrition and Human Health and, College of Food Sciences and Nutritional Engineering, China Agricultural University, Beijing 100193, China
¹¹Medical Research Center, Department of Radiation Oncology, Peking University Third Hospital, Beijing 100191, China
¹²The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710004, China
¹³Departments of Biological Chemistry and Dermatology, School of Medicine, University of California, Irvine, CA 92697, USA
¹⁴Department of Animal Biology, School of Veterinary Medicine, and Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19082, USA
¹⁵Departments of Medicine and Biological Chemistry, University of California, Irvine, CA 92697, USA
^†These authors contributed equally: Yongli Song, Christian F. Guerrero-Juarez, Zhongjian Chen
Correspondence: Zhengquan Yu(zyu@cau.edu.cn)

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.

https://doi.org/10.1038/s41422-020-0334-5

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