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.