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Acute kidney injury promotes development of papillary renal cell adenoma and carcinoma from renal progenitor cells
Science Translational Medicine ( IF 17.161 ) Pub Date : 2020-03-25 , DOI: 10.1126/scitranslmed.aaw6003
Anna Julie Peired, Giulia Antonelli, Maria Lucia Angelotti, Marco Allinovi, Francesco Guzzi, Alessandro Sisti, Roberto Semeraro, Carolina Conte, Benedetta Mazzinghi, Sara Nardi, Maria Elena Melica, Letizia De Chiara, Elena Lazzeri, Laura Lasagni, Tiziano Lottini, Samuela Landini, Sabrina Giglio, Andrea Mari, Fabrizio Di Maida, Alessandro Antonelli, Francesco Porpiglia, Riccardo Schiavina, Vincenzo Ficarra, Davide Facchiano, Mauro Gacci, Sergio Serni, Marco Carini, George J. Netto, Rosa Maria Roperto, Alberto Magi, Christian Fynbo Christiansen, Mario Rotondi, Helen Liapis, Hans-Joachim Anders, Andrea Minervini, Maria Rosaria Raspollini, Paola Romagnani

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.
更新日期:2020-03-26

 

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