Acute kidney injury promotes development of papillary renal cell adenoma and carcinoma from renal progenitor cells
Acute kidney injury promotes development of papillary renal cell adenoma and carcinoma from renal progenitor cells
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DOI：
10.1126/scitranslmed.aaw6003
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发表时间：
2020-03-25
影响因子：
17.1
通讯作者：
Romagnani, Paola
中科院分区：
文献类型：
--
作者：
Peired, Anna Julie;Antonelli, Giulia;Romagnani, Paola
急性组织损伤会导致 DNA 损伤和修复过程，涉及细胞有丝分裂和多倍化的增加，从而导致细胞功能改变，可能会促进癌症的发展。在这里，我们发现急性肾损伤（AKI）会增加人类乳头状肾细胞癌（pRCC）发展和肿瘤复发的风险，多项单中心和多中心研究收集的数据证实了这一点。 AKI 诱导后的肾小管上皮细胞 (TEC) 谱系追踪和对小鼠的长期随访显示，在腺瘤-癌序列中，克隆性乳头状肿瘤的发病具有时间依赖性。在 AKI 相关途径中，人 pRCC 中的 NOTCH1 过度表达与较差的预后相关，并且是 2 型 pRCC 的特异性。在 TEC 中过度表达 NOTCH1 的小鼠会出现乳头状腺瘤和 2 型 pRCC，而 AKI 加速了这一过程。小鼠的谱系追踪鉴定出单个肾祖细胞是乳头状肿瘤的起源细胞。单细胞 RNA 测序表明，人肾祖细胞转录组与 PT1（人 pRCC 的假定起源细胞）有相似之处。此外，NOTCH1 在培养的人肾祖细胞中过度表达可诱导肿瘤样 3D 生长。因此，AKI 可以驱动局部组织祖细胞发生肿瘤。特别是，我们发现 AKI 通过经典的腺瘤-癌序列促进单个祖细胞发展为 pRCC。
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.