Evidence of renal angiomyolipoma neoplastic stem cells arising from renal epithelial cells

Ana Filipa Gonçalves, Mojca Adlesic, Simone Brandt, Tomas Hejhal, Sabine Harlander, Lukas Sommer, Olga Shakhova, Peter J. Wild and Ian J. Frew ()
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Ana Filipa Gonçalves: University of Zurich
Mojca Adlesic: University of Zurich
Simone Brandt: University Hospital Zurich
Tomas Hejhal: University of Zurich
Sabine Harlander: University of Zurich
Lukas Sommer: University of Zurich
Olga Shakhova: University of Zurich
Peter J. Wild: University Hospital Zurich
Ian J. Frew: University of Zurich

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-01514-3

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