RT Journal Article
SR Electronic
T1 Acute kidney injury promotes development of papillary renal cell adenoma and carcinoma from renal progenitor cells
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP eaaw6003
DO 10.1126/scitranslmed.aaw6003
VO 12
IS 536
A1 Peired, Anna Julie
A1 Antonelli, Giulia
A1 Angelotti, Maria Lucia
A1 Allinovi, Marco
A1 Guzzi, Francesco
A1 Sisti, Alessandro
A1 Semeraro, Roberto
A1 Conte, Carolina
A1 Mazzinghi, Benedetta
A1 Nardi, Sara
A1 Melica, Maria Elena
A1 De Chiara, Letizia
A1 Lazzeri, Elena
A1 Lasagni, Laura
A1 Lottini, Tiziano
A1 Landini, Samuela
A1 Giglio, Sabrina
A1 Mari, Andrea
A1 Di Maida, Fabrizio
A1 Antonelli, Alessandro
A1 Porpiglia, Francesco
A1 Schiavina, Riccardo
A1 Ficarra, Vincenzo
A1 Facchiano, Davide
A1 Gacci, Mauro
A1 Serni, Sergio
A1 Carini, Marco
A1 Netto, George J.
A1 Roperto, Rosa Maria
A1 Magi, Alberto
A1 Christiansen, Christian Fynbo
A1 Rotondi, Mario
A1 Liapis, Helen
A1 Anders, Hans-Joachim
A1 Minervini, Andrea
A1 Raspollini, Maria Rosaria
A1 Romagnani, Paola
YR 2020
UL http://stm.sciencemag.org/content/12/536/eaaw6003.abstract
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.