Acute kidney injury promotes development of papillary renal cell adenoma and carcinoma from renal progenitor cells
- 25 March 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 12 (536)
- https://doi.org/10.1126/scitranslmed.aaw6003
Abstract
Acute tissue injury causes DNA damage and repair processes involving increased cell mitosis and polyploidization, leading to cell function alterations that may potentially drive cancer development. Here, we show that acute kidney injury (AKI) increased the risk for papillary renal cell carcinoma (pRCC) development and tumor relapse in humans as confirmed by data collected from several single-center and multicentric studies. Lineage tracing of tubular epithelial cells (TECs) after AKI induction and long-term follow-up in mice showed time-dependent onset of clonal papillary tumors in an adenoma-carcinoma sequence. Among AKI-related pathways, NOTCH1 overexpression in human pRCC associated with worse outcome and was specific for type 2 pRCC. Mice overexpressing NOTCH1 in TECs developed papillary adenomas and type 2 pRCCs, and AKI accelerated this process. Lineage tracing in mice identified single renal progenitors as the cell of origin of papillary tumors. Single-cell RNA sequencing showed that human renal progenitor transcriptome showed similarities to PT1, the putative cell of origin of human pRCC. Furthermore, NOTCH1 overexpression in cultured human renal progenitor cells induced tumor-like 3D growth. Thus, AKI can drive tumorigenesis from local tissue progenitor cells. In particular, we find that AKI promotes the development of pRCC from single progenitors through a classical adenoma-carcinoma sequence.Funding Information
- H2020 European Research Council (648274)
- Fondazione Umberto Veronesi (1931)
- Associazione Italiana per la Ricerca sul Cancro (21821)
This publication has 79 references indexed in Scilit:
- STAR: ultrafast universal RNA-seq alignerBioinformatics, 2012
- Tubule-specific ablation of endogenous β-catenin aggravates acute kidney injury in miceKidney International, 2012
- Acute kidney injuryThe Lancet, 2012
- Identification of novel NRF2-regulated genes by ChIP-Seq: influence on retinoid X receptor alphaNucleic Acids Research, 2012
- Notch in the kidney: development and diseaseThe Journal of Pathology, 2011
- Isolation and Characterization of Progenitor-Like Cells from Human Renal Proximal TubulesThe American Journal of Pathology, 2011
- Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humansJCI Insight, 2010
- Notch Activation Differentially Regulates Renal Progenitors Proliferation and Differentiation Toward the Podocyte Lineage in Glomerular DisordersThe International Journal of Cell Cloning, 2010
- Epidemiology and risk factors for kidney cancerNature Reviews Urology, 2010
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005