PT - JOURNAL ARTICLE AU - Peired, Anna Julie AU - Antonelli, Giulia AU - Angelotti, Maria Lucia AU - Allinovi, Marco AU - Guzzi, Francesco AU - Sisti, Alessandro AU - Semeraro, Roberto AU - Conte, Carolina AU - Mazzinghi, Benedetta AU - Nardi, Sara AU - Melica, Maria Elena AU - De Chiara, Letizia AU - Lazzeri, Elena AU - Lasagni, Laura AU - Lottini, Tiziano AU - Landini, Samuela AU - Giglio, Sabrina AU - Mari, Andrea AU - Di Maida, Fabrizio AU - Antonelli, Alessandro AU - Porpiglia, Francesco AU - Schiavina, Riccardo AU - Ficarra, Vincenzo AU - Facchiano, Davide AU - Gacci, Mauro AU - Serni, Sergio AU - Carini, Marco AU - Netto, George J. AU - Roperto, Rosa Maria AU - Magi, Alberto AU - Christiansen, Christian Fynbo AU - Rotondi, Mario AU - Liapis, Helen AU - Anders, Hans-Joachim AU - Minervini, Andrea AU - Raspollini, Maria Rosaria AU - Romagnani, Paola TI - Acute kidney injury promotes development of papillary renal cell adenoma and carcinoma from renal progenitor cells AID - 10.1126/scitranslmed.aaw6003 DP - 2020 Mar 25 TA - Science Translational Medicine PG - eaaw6003 VI - 12 IP - 536 4099 - http://stm.sciencemag.org/content/12/536/eaaw6003.short 4100 - http://stm.sciencemag.org/content/12/536/eaaw6003.full AB - Tissue injury and repair can contribute to subsequent development of cancer, especially in the setting of chronic damage and repeated cycles of tissue repair. It appears that acute injury may have a similar effect, at least in the kidney. Peired et al. first analyzed data from multiple independent cohorts of human patients and demonstrated a correlation between acute kidney injury and subsequent development of papillary renal cancer and recurrence of cancer in patients who had undergone surgery to remove their initial tumors. The authors then studied human renal progenitor cells and mouse models to determine the underlying mechanism for kidney injury–induced carcinogenesis.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.