胰腺癌肿瘤器官组织的代谢特征表现出亚型特异性差异。

IF 6 3区 医学 Q1 CELL BIOLOGY Cancer & Metabolism Pub Date : 2024-10-03 DOI:10.1186/s40170-024-00357-z
Hassan A Ali, Joanna M Karasinska, James T Topham, Danisha Johal, Steve Kalloger, Andrew Metcalfe, Cassia S Warren, Anthony Miyagi, Lan V Tao, Maya Kevorkova, Shawn C Chafe, Paul C McDonald, Shoukat Dedhar, Seth J Parker, Daniel J Renouf, David F Schaeffer
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引用次数: 0

摘要

背景:胰腺导管腺癌(PDAC)是一种侵袭性很强的疾病,其特点是复杂的代谢重构,能在不断变化的营养供应和氧气条件下生长。基于转录组的预后PDAC肿瘤亚型,即 "基底样 "亚型和 "经典 "亚型,与代谢基因(包括参与糖酵解的基因)表达的差异有关。肿瘤亚型特异性代谢表型可为 PDAC 的治疗开发提供新靶点,但其功能相关性尚未完全阐明。我们的目的是研究基底样肿瘤和典型肿瘤患者的肿瘤模型中代谢谱和转录组的差异:从转移性 PDAC 患者的肿瘤活检组织中建立了患者衍生的器官组织(PDOs),其中包括 3 个基底样肿瘤的 PDOs 和 5 个典型肿瘤的 PDOs。代谢分析包括使用海马糖酵解和线粒体应激试验评估代谢活动的差异,以及 13C 葡萄糖代谢物追踪分析。为了研究线粒体丙酮酸转运对代谢差异的影响,用线粒体丙酮酸载体1(MPC1)抑制剂UK-5099处理PDOs。使用肿瘤组织芯片(TMA)确定了MPC1与可切除PDAC的预后相关性,并对转移性PDAC数据集进行了蛋白质组学分析。对PDAC数据集进行了全基因组和转录组测序、差异基因表达和基因组富集分析:结果:转移性 PDAC PDOs 在糖酵解和氧化磷酸化(OXPHOS)方面表现出亚型特异性差异。基底样肿瘤来源的 PDOs 基线细胞外酸化率较低,但糖酵解储备和耗氧率(OCR)高于经典肿瘤来源的 PDOs。在使用 UK-5099 治疗后,OCR 差异被消除。在 13C- 葡萄糖代谢物追踪实验中,与经典肿瘤 PDO 相比,基底样肿瘤 PDO 的一些 M + 2 代谢物含量较低,但对 UK-5099 介导的 M + 2 代谢物减少的敏感性较高。蛋白质水平分析表明,基底样PDAC病例的MPC1蛋白质水平较低,而低MPC1水平与PDAC肿瘤侵袭性的临床病理参数有关。PDAC差异基因表达分析发现了更多亚型特异性细胞通路和潜在的疾病结局生物标志物:我们的研究结果表明,PDAC亚型的代谢特征各不相同,基底样肿瘤的PDO显示出更高的氧合休克和对MPC1抑制的敏感性。亚型特异性代谢弱点可用于选择性靶向治疗。
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Pancreatic cancer tumor organoids exhibit subtype-specific differences in metabolic profiles.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease characterized by complex metabolic rewiring that enables growth in changing nutrient availability and oxygen conditions. Transcriptome-based prognostic PDAC tumor subtypes, known as 'basal-like' and 'classical' subtypes are associated with differences in metabolic gene expression including genes involved in glycolysis. Tumor subtype-specific metabolism phenotypes may provide new targets for treatment development in PDAC, but their functional relevance has not been fully elucidated. We aimed to investigate differences in metabolic profiles and transcriptomes in tumor models derived from patients with basal-like and classical tumors.

Methods: Patient-derived organoids (PDOs) were established from tumor biopsies collected from patients with metastatic PDAC, including three PDOs from basal-like and five PDOs from classical tumors. Metabolic analyses included assessment of differences in metabolic activity using Seahorse Glycolysis and Mito Stress tests and 13C-glucose metabolites tracing analysis. In order to investigate the influence of mitochondrial pyruvate transport on metabolic differences, PDOs were treated with the mitochondrial pyruvate carrier 1 (MPC1) inhibitor UK-5099. Prognostic relevance of MPC1 was determined using a tumor tissue microarray (TMA) in resectable, and proteomics profiling in metastatic PDAC datasets. Whole genome and transcriptome sequencing, differential gene expression and gene set enrichment analyses were performed in PDOs.

Results: Metastatic PDAC PDOs showed subtype-specific differences in glycolysis and oxidative phosphorylation (OXPHOS). Basal-like tumor-derived PDOs had a lower baseline extracellular acidification rate, but higher glycolytic reserves and oxygen consumption rate (OCR) than classical tumor-derived PDOs. OCR difference was eliminated following treatment with UK-5099. In the 13C-glucose metabolites tracing experiment, a basal-like tumor PDO showed lower fractions of some M + 2 metabolites but higher sensitivity to UK-5099 mediated reduction in M + 2 metabolites than a classical tumor PDO. Protein level analyses revealed lower MPC1 protein levels in basal-like PDAC cases and association of low MPC1 levels with clinicopathologic parameters of tumor aggressiveness in PDAC. PDO differential gene expression analyses identified additional subtype-specific cellular pathways and potential disease outcome biomarkers.

Conclusions: Our findings point to distinct metabolic profiles in PDAC subtypes with basal-like tumor PDOs showing higher OXPHOS and sensitivity to MPC1 inhibition. Subtypes-specific metabolic vulnerabilities may be exploited for selective therapeutic targeting.

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来源期刊
自引率
1.70%
发文量
17
审稿时长
14 weeks
期刊介绍: Cancer & Metabolism welcomes studies on all aspects of the relationship between cancer and metabolism, including: -Molecular biology and genetics of cancer metabolism -Whole-body metabolism, including diabetes and obesity, in relation to cancer -Metabolomics in relation to cancer; -Metabolism-based imaging -Preclinical and clinical studies of metabolism-related cancer therapies.
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