Background/Objectives: Clear-cell renal cell carcinoma (ccRCC) is a heterogenous disease that can be classified into multiple molecular subtypes with differential prognosis and sensitivities to treatments based on their genomic, transcriptomic, proteomic, and metabolic profiles. Patient-derived xenografts (PDXs) are high-fidelity cancer models because they maintain similar genotypes and immunohistologic phenotypes to the parental tumors and respond to standard-of-care therapies as expected. However, whether the molecular subtypes identified in ccRCC patient samples are preserved in PDX models is not clear. Our objective is to compare the transcriptional and proteomic profiles of our PDX models to those of ccRCC patients and identify both similarities and distinctions between molecular profiles of PDX subtypes and corresponding ccRCC patient subtypes, so that proper PDX subtypes can be used when investigating the corresponding ccRCC patient subtypes.Methods: To match PDXs to the human ccRCC molecular subtypes, we compared the transcriptomic and proteomic profiles of five ccRCC PDX models established in our lab to those of the human ccRCC molecular subtypes reported by our group, as well as other groups, using hierarchical analysis, Principal Component Analysis (PCA), and Permutation Correlation Analysis. The enrichment of key molecular pathways in PDXs and ccRCC subtypes was determined using Gene Set Enrichment Analysis.Results: We found that each PDX resembles one of the molecular subtypes closely at both transcript and protein levels. In addition, PDXs representing different molecular subtypes show unique metabolic characteristics. Moreover, molecular subtypes of PDXs correlated with ccRCC patient subtypes in key pathway activities implicated in ccRCC progression and therapy resistance.Conclusions: Our results suggest that PDX subtypes should be used when investigating the molecular mechanism of cancer progression and therapy resistance for corresponding ccRCC patient subtypes. This “matching” strategy will greatly facilitate the clinical translation of positive findings into the optimal management of ccRCC patients.
背景/目的：透明细胞肾细胞癌（ccRCC）是一种异质性疾病，可根据其基因组、转录组、蛋白质组和代谢特征分为多种分子亚型，这些亚型在预后和治疗敏感性上存在差异。患者来源的异种移植模型（PDXs）因其保持了与亲本肿瘤相似的基因型和免疫组织学表型，并能按预期对标准治疗方案产生反应，被认为是高保真度的癌症模型。然而，在ccRCC患者样本中鉴定的分子亚型是否在PDX模型中得以保留尚不明确。本研究旨在比较PDX模型与ccRCC患者的转录组和蛋白质组特征，识别PDX亚型与对应ccRCC患者亚型在分子特征上的相似性与差异性，从而在探究相应ccRCC患者亚型时能够选用合适的PDX亚型模型。 方法：为将PDXs与人类ccRCC分子亚型进行匹配，我们采用层次聚类分析、主成分分析（PCA）及置换相关分析等方法，将本实验室建立的五种ccRCC PDX模型的转录组和蛋白质组特征，与本团队及其他研究团队已报道的人类ccRCC分子亚型特征进行比较。通过基因集富集分析确定PDXs与ccRCC亚型中关键分子通路的富集情况。 结果：研究发现，每个PDX模型在转录水平和蛋白质水平均与某一分子亚型高度相似。此外，代表不同分子亚型的PDXs展现出独特的代谢特征。更重要的是，PDXs的分子亚型与ccRCC患者亚型在涉及ccRCC进展和治疗耐药的关键通路活性上具有相关性。 结论：我们的研究结果表明，在探究对应ccRCC患者亚型的癌症进展和治疗耐药分子机制时，应采用匹配的PDX亚型模型。这种“匹配”策略将极大促进将阳性研究发现转化为ccRCC患者优化治疗的临床转化进程。
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