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

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.

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Fig. 1: Characterization of the epithelial macroenvironment of EMPD skin using 3′-end scRNA-seq.
Fig. 2: Ectopic Msi1 overexpression results in Paget-like phenotype in murine skin.
Fig. 3: Characterization of Paget-like cells in DTG murine skin epidermis using 3′-end scRNA-seq.
Fig. 4: RNA dynamics and lineage tracing analyses favor the basal keratinocyte-Paget cell in situ transformation theory.
Fig. 5: Murine Msi1-induced Paget-like skin and EMPD human skin share common molecular signaling pathways.
Fig. 6: Msi1 activates Her2 signaling pathway.
Fig. 7: Msi1 activates mTOR signaling pathway.
Fig. 8: Topical Rapamycin treatment effectively alleviates PD-associated pathological symptoms in a cohort of human EMPD patients.

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Acknowledgements

Z. Yu is supported by the National Natural Science Foundation of China (81772984, 81572614); Beijing Nature Foundation Grant (5162018); the Major Project for Cultivation Technology (2016ZX08008001, 2014ZX08008001); Basic Research Program (2019TC227, 2019TC088); and SKLB Open Grant (2020SKLAB6–18). B.A. is supported by a NIH Grant R01AR42288. M.V.P. is supported by a Pew Charitable Trust Grant, NIH Grants R01-AR067273 and R01-AR069653, NSF Grant DMS1763272, and Simons Foundation Grant (594598, Q.N.). This work is also supported by NIH grants U01-AR073159 (to Q.N., M.V.P., and X.D.) and U54-CA217378 (to Arthur Lander, John Lowengrub, and Marian Waterman). Q.N. is also supported by NSF grants DMS176372 and DMS1562176, the Jayne Koskinas Ted Giovanis Foundation for Health and Policy jointly with the Breast Cancer Research Foundation, and NSF-Simons Foundation (594598). C.F.G.-J. is supported by UC Irvine Chancellor’s ADVANCE Postdoctoral Fellowship Program, NSF-Simons Postdoctoral Fellowship, NSF Grant DMS1763272, and Simons Foundation Grant (594598, Q.N.) and a kind gift from the Howard Hughes Medical Institute Hanna H. Gray Postdoctoral Fellowship Program. G.Z. is supported by the Key Project of the National Natural Science Foundation of China (81830093) and the CAMS Innovation Fund for Medical Sciences (CIFMS; No. 2019-I2M-1-003).

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Z. Yu designed research; Y.S., C.F.G.-J., Z.C., Y. Tang, X.M., C.L., X.B., M.D., L.B., Y. Tian, R.L., R.Z., J.X., X.S., S.D., Y.L., Y. Zhu and S.S. performed research; C.F.G-J. performed scRNA-seq and bioinformatic analyses and curated scRNA-seq data; Q.N. and Z. Yu supervised scRNA-seq and bioinformatic analyses; Y.S., C.F.G.-J., H.C., G.Z., J.S., F.R., L.X., Z. Ying, Y. Zhao, X.D., C.J.L., B.A., M.V.P, Q.N., and Z. Yu analyzed data; C.F.G-J. and Y.S. produced figures; C.F.G.-J., Y.S., Q.N., M.V.P. and Z. Yu wrote the manuscript.

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Correspondence to Zhengquan Yu.

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Song, Y., Guerrero-Juarez, C.F., Chen, Z. et al. The Msi1-mTOR pathway drives the pathogenesis of mammary and extramammary Paget’s disease. Cell Res 30, 854–872 (2020). https://doi.org/10.1038/s41422-020-0334-5

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