Evidence of renal angiomyolipoma neoplastic stem cells arising from renal epithelial cells.
- Gonçalves AF Institute of Physiology, University of Zurich, 8057, Zurich, Switzerland.
- Adlesic M Institute of Physiology, University of Zurich, 8057, Zurich, Switzerland.
- Brandt S Department of Pathology and Molecular Pathology, University Hospital Zurich, 8091, Zurich, Switzerland.
- Hejhal T Institute of Physiology, University of Zurich, 8057, Zurich, Switzerland.
- Harlander S Institute of Physiology, University of Zurich, 8057, Zurich, Switzerland.
- Sommer L Institute of Anatomy, University of Zurich, 8057, Zurich, Switzerland.
- Shakhova O Institute of Anatomy, University of Zurich, 8057, Zurich, Switzerland.
- Wild PJ Department of Pathology and Molecular Pathology, University Hospital Zurich, 8091, Zurich, Switzerland.
- Frew IJ Institute of Physiology, University of Zurich, 8057, Zurich, Switzerland. ian.frew@uniklinik-freiburg.de.
- 2017-11-15
Published in:
- Nature communications. - 2017
Angiomyolipoma
Animals
Cell Differentiation
Epithelial Cells
Humans
Kidney Neoplasms
Kidney Tubules, Proximal
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, SCID
Neoplasm Transplantation
Neoplastic Stem Cells
RNA Interference
RNA, Small Interfering
Spheroids, Cellular
TOR Serine-Threonine Kinases
Transplantation, Heterologous
Tuberous Sclerosis Complex 1 Protein
Tuberous Sclerosis Complex 2 Protein
Tumor Cells, Cultured
Tumor Suppressor Proteins
English
Renal angiomyolipomas (AML) contain an admixture of clonal tumour cells with features of several different mesenchymal lineages, implying the existence of an unidentified AML neoplastic stem cell. Biallelic inactivation of TSC2 or TSC1 is believed to represent the driving event in these tumours. Here we show that TSC2 knockdown transforms senescence-resistant cultured mouse and human renal epithelial cells into neoplastic stem cells that serially propagate renal AML-like tumours in mice. mTOR inhibitory therapy of mouse AML allografts mimics the clinical responses of human renal AMLs. Deletion of Tsc1 in mouse renal epithelia causes differentiation in vivo into cells expressing characteristic AML markers. Human renal AML and a renal AML cell line express proximal tubule markers. We describe the first mouse models of renal AML and provide evidence that these mesenchymal tumours originate from renal proximal tubule epithelial cells, uncovering an unexpected pathological differentiation plasticity of the proximal tubule.
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.1038/s41467-017-01514-3
- PMID 29133867
- Persistent URL
- https://sonar.ch/global/documents/266568
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