Proteomic characterization of the pseudocapsule of clear cell renal cell carcinoma in VHL disease reveals a distinct microenvironment at the tumor boundary zone

IF 7.7 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia Pub Date : 2025-08-05 DOI:10.1016/j.neo.2025.101214

Tobias Feilen , Manuel Rogg , Grigor Andreev , Niko Pinter , Maximilian Wess , Anna L. Kössinger , Nastasja Diel , Elke Neumann-Haefelin , Athina Ganner , Markus Grabbert , Christoph Schell , Oliver Schilling

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引用次数: 0

Abstract

Von Hippel-Lindau (VHL) disease describes a hereditary tumor predisposition syndrome, caused by germline mutations in the VHL tumor suppressor gene, resulting in the functional loss of the VHL protein (pVHL). pVHL loss translates into a pseudo-hypoxic state that drives clear cell renal cell carcinoma (ccRCC) development. ccRCC tumors frequently form a pseudocapsule (PC) at the tumor boundary. This study describes the first comprehensive proteomic analysis of the PC in ccRCC patients with hereditary VHL inactivation, revealing a distinctive matrisomal signature. We conducted a deep, mass spectrometry-based proteomic analysis of 130 formalin-fixed paraffin-embedded (FFPE) ccRCC samples, comprising 54 tumor, 45 PC, and 31 non-malignant adjacent tissue (NAT) specimens from 34 patients. The PC exhibited unique matrisomal features, with pronounced enrichment of structural extracellular matrix (ECM) components, ECM processing enzymes, and secreted signaling proteins such as TGFβ2. Its proteome composition, including proteins involved in immune response, varied with tumor size and semi-tryptic peptide analysis indicated selective ECM processing in the PC and elevated levels of proteolysis within the tumor. Further, tumor proteomes reflected canonical VHL-driven metabolic reprogramming, including upregulated glycolysis and hypoxia markers, suppressed aerobic metabolism, and dysregulated fatty acid metabolism. Enriched immunoproteasome, MHC-I, and inflammasome proteins indicated an active immune response. Pro-angiogenic factors enriched in the tumor partially extended into the PC. Comparison of primary vs metachronous ccRCC cases uncovered proteomic tumor plasticity in VHL disease. Together, our study delineates the PC as an active, signaling-rich compartment at the ccRCC boundary with potential implications for tumor progression and clinical relevance beyond a mere structural scaffold.

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VHL疾病透明细胞肾细胞癌假包膜的蛋白质组学特征揭示了肿瘤边界区独特的微环境

Von Hippel-Lindau （VHL）病描述了一种遗传性肿瘤易感性综合征，由VHL肿瘤抑制基因的种系突变引起，导致VHL蛋白（pVHL）的功能丧失。pVHL缺失转化为假性缺氧状态，驱动透明细胞肾细胞癌（ccRCC）的发展。ccRCC肿瘤常在肿瘤边界形成假包膜（PC）。这项研究首次对遗传性VHL失活的ccRCC患者的PC进行了全面的蛋白质组学分析，揭示了一个独特的基质特征。我们对来自34例患者的130例福尔马林固定石蜡包埋（FFPE） ccRCC样本进行了深入的、基于质谱的蛋白质组学分析，其中包括54例肿瘤、45例PC和31例非恶性邻近组织（NAT）样本。PC表现出独特的基质特征，其结构细胞外基质（ECM）成分、ECM加工酶和分泌的信号蛋白如tgf - β2显著富集。它的蛋白质组组成，包括参与免疫反应的蛋白质，随着肿瘤大小的变化而变化，半色氨酸肽分析表明，PC中选择性ECM加工和肿瘤内蛋白水解水平升高。此外，肿瘤蛋白质组反映了典型的vhl驱动的代谢重编程，包括糖酵解和缺氧标记上调、有氧代谢抑制和脂肪酸代谢失调。丰富的免疫蛋白酶体、mhc - 1和炎性小体蛋白表明免疫反应活跃。肿瘤中富集的促血管生成因子部分延伸至前列腺癌。原发性和异时性ccRCC病例的比较揭示了VHL疾病中蛋白质组学肿瘤的可塑性。总之，我们的研究将PC描述为ccRCC边界上一个活跃的、富含信号的隔室，它对肿瘤进展和临床相关性具有潜在的影响，而不仅仅是一个结构支架。

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来源期刊

Neoplasia 医学-肿瘤学

CiteScore

9.20

自引率

2.10%

发文量

审稿时长

26 days

期刊介绍： Neoplasia publishes the results of novel investigations in all areas of oncology research. The title Neoplasia was chosen to convey the journal’s breadth, which encompasses the traditional disciplines of cancer research as well as emerging fields and interdisciplinary investigations. Neoplasia is interested in studies describing new molecular and genetic findings relating to the neoplastic phenotype and in laboratory and clinical studies demonstrating creative applications of advances in the basic sciences to risk assessment, prognostic indications, detection, diagnosis, and treatment. In addition to regular Research Reports, Neoplasia also publishes Reviews and Meeting Reports. Neoplasia is committed to ensuring a thorough, fair, and rapid review and publication schedule to further its mission of serving both the scientific and clinical communities by disseminating important data and ideas in cancer research.