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

Abstract

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.

Human kidney clonal proliferation disclose lineage-restricted precursor characteristics

“…These molecules www.nature.com/scientificreports/ were overexpressed in FL clones along with ITGA5, GGT1, CDH6 and CA9 all previously shown to be highly expressed by clear cell RCC 24,[42][43][44][45] . Thus, intriguingly proximal clonal proliferation and behavior may be viewed as precursor cell lesion for RCC 46 . Oxidative phosphorylation, respiratory chain, mitochondrial matrix and envelope genes were also significantly elevated in FL clones.…”

Single cell transcriptional and chromatin accessibility profiling redefine cellular heterogeneity in the adult human kidney

“…These cells have a distinct morphology and expression profile and undergo expansion after acute kidney injury 19 . Furthermore, they have reported potential for tubular and podocyte regeneration [20][21][22][23] and have been implicated in the development of renal cell carcinoma 24 . However, the sparsity of these cells has hampered further characterization.…”

Molecular Mechanisms of Renal Progenitor Regulation: How Many Pieces in the Puzzle?

“…CD133+CD24+ cells are localized at the urinary pole of the Bowman capsule, as well as scattered along the tubular compartment of the nephron among differentiated tubular cells [ 6 ]. Some renal progenitors, including those localized in the Bowman capsule and a subset of the ones scattered along the tubule, also express CD106 (also called vascular cell adhesion molecule 1, VCAM1), while the majority of progenitors localized along the tubule do not [ 6 , 8 ]. These phenotypical differences reflect a diverse functional capacity; indeed, CD133+CD24+CD106- cells scattered along the tubules display functional features of tubular progenitors, while CD133+CD24+CD106+ parietal epithelial cells (PECs) are multipotent [ 6 ].…”