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The Msi1-mTOR pathway drives the pathogenesis of mammary and extramammary Paget’s disease
- 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.
- Subjects :
- Adult
Male
musculoskeletal diseases
Genetically modified mouse
Cell
Breast Neoplasms
Nerve Tissue Proteins
Biology
Extramammary Paget's disease
Article
Pathogenesis
Mice
03 medical and health sciences
0302 clinical medicine
otorhinolaryngologic diseases
medicine
Skin cancer
Animals
Humans
Molecular Biology
PI3K/AKT/mTOR pathway
Aged
030304 developmental biology
Sirolimus
0303 health sciences
Antibiotics, Antineoplastic
TOR Serine-Threonine Kinases
RNA-Binding Proteins
Cancer
Cell Biology
Middle Aged
medicine.disease
Paget Disease, Extramammary
medicine.anatomical_structure
TOR signalling
Cancer research
Female
Signal transduction
Biomarkers
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 17487838 and 10010602
- Volume :
- 30
- Database :
- OpenAIRE
- Journal :
- Cell Research
- Accession number :
- edsair.doi.dedup.....6261562f960dd160830d142877a8f257