ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: FR-PO1006

AKI Promotes the Development of Papillary Renal Carcinoma from Tubular Progenitors

Session Information

  • Onco-Nephrology: Basic
    November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Onco-Nephrology

  • 1500 Onco-Nephrology

Authors

  • Peired, Anna Julie, University of Florence, Florence, Italy
  • Allinovi, Marco, Meyer Children's Hospital, Firenze, Italy
  • Angelotti, Maria Lucia, Excellence Center for Research, Transfer and High Education Denothe, University of Florence, Florence, Italy
  • Antonelli, Giulia, University of Florence, Firenze, Italy
  • Guzzi, Francesco, University of Florence, Firenze, Italy
  • Romagnani, Paola, University of Florence, Firenze, Italy
Background

Renal cell carcinoma (RCC) accounts for about 2% of all cancers. Risk factors for RCC include obesity, diabetes, hypertension and genetic factors, but the majority of cancers occur in apparent absence of clear risk factors. As tissue injury is an important cofactor for many types of cancers, we propose to verify if acute kidney injury (AKI) plays a role in RCC development, and to identify the cellular origin of RCC.

Methods

We used the following techniques: 1. Experimental AKI induction in wild-type mice to study tumor development over 36 weeks. 2. Analysis of TCGA Research Network dataset on human papillary RCC (pRCC) molecular characterization, focusing on AKI-driven pathways. 3. Development of mouse models in which the intracellular domain of Notch 1 (NICD1) a molecule modulated during AKI, is expressed constitutively by all Pax8+ tubular epithelial cells (Pax8/NICD1) or only by Pax2+ renal progenitors (Pax2/NICD1) upon induction in adult mice. The mice were sacrificed at 36 weeks or 4 weeks after AKI. 4. Clonal analysis of tumoral lesions with Confetti reporter. 5. Examination of single cell RNA sequencing (RNAseq) data from pRCC patients.

Results

Wild-type mice subjected to AKI developed type 2 papillary adenomas and pRCCs over time. Among AKI-related pathways, Notch1 overexpression in human pRCC associated with worse outcome, prompting us to generate NICD1-overexpressing mice. At 36 weeks or at 4 weeks following AKI, Pax8/NICD1 mice presented a significant decline of renal function as well as type 2 pRCCs. Confetti lineage tracing showed that most of the pRCCs were mono- or biclonal, suggesting a local stem cell/progenitor cell origin. Pax2/NICD1 mice presented type 2 pRCCs, and lineage tracing identified single Pax2+ tubular progenitors as the source of pRCCs. RNAseq analysis confirmed that PT1 signature of pRCC cell of origin matched human tubular progenitor molecular characteristics.

Conclusion

AKI promotes long-term development of type 2 papillary tumors in mice by activating AKI-associated pathway Notch1. This study establishes Pax2+ renal progenitors as the cellular origin of the tumor in mice, and identifies renal progenitors as pRCC PT1 signature cells in humans.

Funding

  • Government Support - Non-U.S.