PO.TB09.01 · 肿瘤生物学
空间多模态和功能解析揭示透明细胞肾细胞癌中UCHL1驱动的恶性程序
Spatial multimodal and functional dissection reveal a UCHL1-driven malignant program in clear cell renal cell carcinoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
透明细胞肾细胞癌（ccRCC）是肾癌最常见的亚型，表现出显著的分子和空间异质性，这促成了治疗耐药和不良临床结局。我们既往的工作将UCHL1鉴定为侵袭性ccRCC的标记物，但其在肿瘤进展中的机制作用仍不清楚。为进一步阐明UCHL1的功能，我们将来自67个肿瘤的单核RNA测序（snRNA-seq）与批量蛋白基因组学以及针对分子覆盖度和空间特异性的空间检测相整合。我们优化后的肿瘤内在UCHL1分类鉴定出一个以UCHL1 mRNA和蛋白丰度升高为特征的独特ccRCC亚组。UCHL1高表达亚组占该队列中肿瘤的19%，与BAP1突变体、免疫浸润和不良预后显著相关。Xenium中的空间定位表明UCHL1高表达肿瘤显示出与免疫炎性肿瘤微环境（TME）的增强相互作用，而UCHL1低表达肿瘤则富集于由内皮和VEGF信号主导的免疫荒漠区域。此外，我们观察到UCHL1表达的空间动态源自同一肿瘤内不同的亚克隆，反映了UCHL1高表达亚组中的瘤内异质性。我们的功能研究证明，UCHL1敲除和下调在体外及细胞系来源异种移植物（CDX）模型中显著抑制ccRCC细胞增殖和成瘤性。UCHL1的药理性抑制在ccRCC细胞系中持续减少肿瘤生长。相应的细胞系蛋白质组学和翻译后修饰分析（包括磷酸化和泛素化）阐明UCHL1通过NF-κB激活调控炎症和上皮-间充质转化（EMT）等关键的促肿瘤通路。值得注意的是，RESL9患者来源异种移植物（PDX）模型对UCHL1抑制剂反应强烈，表现出显著的肿瘤生长抑制。总之，这些发现确立UCHL1为ccRCC中一个关键的分子驱动因素和治疗靶点，支持UCHL1导向的单药治疗或联合方案改善晚期ccRCC患者结局的潜力。
查看英文原文 English abstract
Clear cell renal cell carcinoma (ccRCC), the most common subtype of kidney cancer, exhibits substantial molecular and spatial heterogeneity that contributes to therapeutic resistance and poor clinical outcomes. Our previous work identified UCHL1 as a marker of aggressive ccRCC, but its mechanistic role in tumor progression remained unclear. To further elucidate UCHL1 function, we integrated single-nucleus RNA sequencing (snRNA-seq) from 67 tumors with bulk proteogenomics and spatial assays addressing molecular coverage and spatial specificity. Our refined tumor-intrinsic UCHL1 classification identified a distinct ccRCC subgroup characterized by elevated UCHL1 mRNA and protein abundance. The UCHL1-high subgroup, comprising 19% of tumors in this cohort, was significantly associated with BAP1 mutants, immune infiltration, and poor prognosis. The spatial mapping in Xenium indicated UCHL1-high tumors displayed enhanced interactions with an immune-inflamed tumor microenvironment (TME), whereas UCHL1-low tumors were enriched for immune-desert regions dominated by endothelium and VEGF signaling. Furthermore, we observed spatial dynamics in UCHL1 expression arising from distinct subclones within the same tumor, reflecting the intratumoral heterogeneity in the UCHL1-high subgroup. Our functional studies demonstrated that UCHL1 knockout and downregulation markedly suppressed ccRCC cell proliferation and tumorigenicity in vitro and in cell line-derived xenograft (CDX) models. Pharmacological inhibition of UCHL1 consistently reduced tumor growth in ccRCC cell lines. The corresponding cell line proteomics and post-translational modification profiling, including phosphorylation and ubiquitination, delineated that UCHL1 regulated key tumor-promoting pathways of inflammation and epithelial-mesenchymal transition (EMT) through NF-κB activation. Notably, the RESL9 patient-derived xenograft (PDX) model responded robustly to the UCHL1 inhibitor, exhibiting pronounced tumor growth suppression. Collectively, these findings establish UCHL1 as a critical molecular driver and therapeutic target in ccRCC, supporting the potential of UCHL1-directed monotherapies or combination regimens to improve outcomes for patients with advanced ccRCC.
利益披露 Disclosure
Y. Li, None..
W. Caravan, None..
X. Wei, None..
K. B. Dhami, None..
K. Sato, None..
X. Fang, None..
P. Lal, None..
H. Liu, None..
L. Chen, None..
C. Weimholt, None..
H. Zhang, None..
L. Ding, None..
F. Chen, None.