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Acute kidney injury promotes development of papillary renal cell adenoma and carcinoma from renal progenitor cells

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  • Anna Julie Peired, Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence 50139, Italy.
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  • Giulia Antonelli, Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence 50139, Italy.
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  • Maria Lucia Angelotti, Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence 50139, Italy.
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  • Marco Allinovi, Nephrology, Dialysis and Transplantation Unit, Careggi University Hospital, Florence 50139, Italy.
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  • Francesco Guzzi, Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence 50139, Italy.
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  • Alessandro Sisti, Nephrology and Dialysis Unit, Meyer Children's University Hospital, Florence 50139, Italy.
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  • Roberto Semeraro, Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence 50139, Italy.
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  • Carolina Conte, Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence 50139, Italy.
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  • Benedetta Mazzinghi, Nephrology and Dialysis Unit, Meyer Children's University Hospital, Florence 50139, Italy.
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  • Sara Nardi, Nephrology and Dialysis Unit, Meyer Children's University Hospital, Florence 50139, Italy.
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  • Maria Elena Melica, Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence 50139, Italy.
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  • Letizia De Chiara, Nephrology and Dialysis Unit, Meyer Children's University Hospital, Florence 50139, Italy.
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  • Elena Lazzeri, Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence 50139, Italy.
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  • Laura Lasagni, Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence 50139, Italy.
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  • Tiziano Lottini, Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Florence 50139, Italy.
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  • Samuela Landini, Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence 50139, Italy.
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  • Sabrina Giglio, Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence 50139, Italy.
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  • Andrea Mari, Department of Urology, Careggi Hospital, University of Florence, Florence 50139, Italy.
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  • Fabrizio Di Maida, Department of Urology, Careggi Hospital, University of Florence, Florence 50139, Italy.
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  • Alessandro Antonelli, Department of Urology, Spedali Civili Hospital, University of Brescia, Brescia 25123, Italy.
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  • Francesco Porpiglia, Department of Urology, University of Turin, San Luigi Gonzaga Hospital, Orbassano, Turin 10043, Italy.
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  • Riccardo Schiavina, Department of Urology, S. Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy.
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  • Vincenzo Ficarra, Department of Urology, University of Padua, Padua 35122, Italy.
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  • Davide Facchiano, Department of Urology, Careggi Hospital, University of Florence, Florence 50139, Italy.
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  • Mauro Gacci, Department of Urology, Careggi Hospital, University of Florence, Florence 50139, Italy.
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  • Sergio Serni, Department of Urology, Careggi Hospital, University of Florence, Florence 50139, Italy.
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  • Marco Carini, Department of Urology, Careggi Hospital, University of Florence, Florence 50139, Italy.
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  • George J Netto, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
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  • Rosa Maria Roperto, Nephrology and Dialysis Unit, Meyer Children's University Hospital, Florence 50139, Italy.
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  • Alberto Magi, Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence 50139, Italy.
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  • Christian Fynbo Christiansen
  • Mario Rotondi, Unit of Internal Medicine and Endocrinology, ICS Maugeri I.R.C.C.S., Scientific Institute of Pavia, Pavia 28100, Italy.
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  • Helen Liapis, Arkana Laboratories, Little Rock, AR 72211, USA.
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  • Hans-Joachim Anders, Division of Nephrology, Medizinische Klinik and Poliklinik IV, Klinikum der LMU München, Munich 80336, Germany.
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  • Andrea Minervini, Department of Urology, Careggi Hospital, University of Florence, Florence 50139, Italy.
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  • Maria Rosaria Raspollini, Histopathology and Molecular Diagnostics, University Hospital Careggi, Florence 50139, Italy.
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  • Paola Romagnani, Nephrology and Dialysis Unit, Meyer Children's University Hospital, Florence 50139, Italy.

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.

Original languageEnglish
Article numbereaaw6003
JournalScience Translational Medicine
Volume12
Issue536
Number of pages16
ISSN1946-6234
DOIs
Publication statusPublished - 2020

    Research areas

  • ABLATION, DISEASE, GROWTH, NOTCH, PATHWAY, PROTECTS, RECEPTOR, RECURRENCE, REGENERATION, TUMORS

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