State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, Human Phenome Institute, Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 200433, China.
Department of Cardiothoracic Surgery, Second Hospital of Anhui Medical University, and Cardiovascular Research Center, Anhui Medical University, Hefei, 230601, China.
Nat Commun. 2023 Sep 13;14(1):5670. doi: 10.1038/s41467-023-41139-3.
The progression of urothelial bladder cancer (UC) is a complicated multi-step process. We perform a comprehensive multi-omics analysis of 448 samples from 190 UC patients, covering the whole spectrum of disease stages and grades. Proteogenomic integration analysis indicates the mutations of HRAS regulated mTOR signaling to form urothelial papilloma rather than papillary urothelial cancer (PUC). DNA damage is a key signaling pathway in the progression of carcinoma in situ (CIS) and related to APOBEC signature. Glucolipid metabolism increase and lower immune cell infiltration are associated with PUC compared to CIS. Proteomic analysis distinguishes the origins of invasive tumors (PUC-derived and CIS-derived), related to distinct clinical prognosis and molecular features. Additionally, loss of RBPMS, associated with CIS-derived tumors, is validated to increase the activity of AP-1 and promote metastasis. This study reveals the characteristics of two distinct branches (PUC and CIS) of UC progression and may eventually benefit clinical practice.
尿路上皮膀胱癌（UC）的进展是一个复杂的多步骤过程。我们对来自 190 名 UC 患者的 448 个样本进行了全面的多组学分析，涵盖了疾病的整个阶段和分级。蛋白质基因组整合分析表明，HRAS 调节的 mTOR 信号的突变导致形成尿路上皮乳头瘤而不是乳头状尿路上皮癌（PUC）。DNA 损伤是原位癌（CIS）进展中的关键信号通路，与 APOBEC 特征有关。与 CIS 相比，糖脂代谢增加和免疫细胞浸润减少与 PUC 有关。蛋白质组学分析区分了侵袭性肿瘤（PUC 衍生和 CIS 衍生）的起源，与不同的临床预后和分子特征有关。此外，与 CIS 衍生肿瘤相关的 RBPMS 缺失被证实可增加 AP-1 的活性并促进转移。本研究揭示了 UC 进展的两个不同分支（PUC 和 CIS）的特征，最终可能有益于临床实践。
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