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Lineage analysis of basal epithelial cells reveals their unexpected plasticity and supports a cell-of-origin model for prostate cancer heterogeneity

Abstract

A key issue in cancer biology is whether oncogenic transformation of different cell types of origin within an adult tissue gives rise to distinct tumour subtypes that differ in their prognosis and/or treatment response. We now show that initiation of prostate tumours in basal or luminal epithelial cells in mouse models results in tumours with distinct molecular signatures that are predictive of human patient outcomes. Furthermore, our analysis of untransformed basal cells reveals an unexpected assay dependence of their stem cell properties in sphere formation and transplantation assays versus genetic lineage tracing during prostate regeneration and adult tissue homeostasis. Although oncogenic transformation of basal cells gives rise to tumours with luminal phenotypes, cross-species bioinformatic analyses indicate that tumours of luminal origin are more aggressive than tumours of basal origin, and identify a molecular signature associated with patient outcome. Our results reveal the inherent plasticity of basal cells, and support a model in which different cells of origin generate distinct molecular subtypes of prostate cancer.

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Figure 1: High frequency of prostate basal stem/progenitor cells in sphere formation and tissue reconstitution assays.
Figure 2: Detection of rare bipotential basal progenitors during prostate regeneration in vivo.
Figure 3: Detection of rare bipotential basal progenitors during prostate homeostasis.
Figure 4: Basal cells are a cell type of origin for prostate tumours.
Figure 5: A luminal origin gene signature that is prognostic for human prostate cancer outcome.
Figure 6: Two models for prostate epithelial lineage relationships and cell of origin for cancer.

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Acknowledgements

We thank J. Rock and B. Hogan (Duke University Medical School, USA) for their generous gift of CK5–CreERT2 transgenic mice, O. Couronne and the Columbia University Genome Sequencing Facility for RNA-seq analysis, and R. DePinho (MD Anderson Cancer Center) for assistance in obtaining the Glinsky data set. This work was supported by a postdoctoral fellowship from the DOD Prostate Cancer Research Program (Z.A.W.), a postdoctoral Computing Innovation Fellowship (CIFellow) from NSF, CRA and CCC (A.M.), and by grants from the National Institutes of Health (C.A-S., A.C. and M.M.S.).

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Z.A.W. carried out mouse experiments, Z.A.W. and S.K.B. performed transplantation experiments, A.M. performed bioinformatic analyses, and R.D.C. analysed tumour histology. Z.A.W. and M.M.S. designed the overall study, C.A-S., R.D.C., A.C. and M.M.S. supervised the data analysis, and Z.A.W., A.M. and M.M.S. wrote the manuscript, in consultation with C.A-S. and A.C. All authors provided discussion and comments on the manuscript.

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Correspondence to Michael M. Shen.

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The authors declare no competing financial interests.

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Wang, Z., Mitrofanova, A., Bergren, S. et al. Lineage analysis of basal epithelial cells reveals their unexpected plasticity and supports a cell-of-origin model for prostate cancer heterogeneity. Nat Cell Biol 15, 274–283 (2013). https://doi.org/10.1038/ncb2697

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