蛋白质代谢组学和患者肿瘤切片实验表明,氨基酸是纤维乳头状癌线粒体重新配线的核心。

IF 11.7 1区 医学 Q1 CELL BIOLOGY Cell Reports Medicine Pub Date : 2024-09-17 Epub Date: 2024-08-28 DOI:10.1016/j.xcrm.2024.101699
Donald Long, Marina Chan, Mingqi Han, Zeal Kamdar, Rosanna K Ma, Pei-Yin Tsai, Adam B Francisco, Joeva Barrow, David B Shackelford, Mark Yarchoan, Matthew J McBride, Lukas M Orre, Nathaniel M Vacanti, Taranjit S Gujral, Praveen Sethupathy
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引用次数: 0

摘要

纤维母细胞瘤(FLC)是一种罕见、致命、早发的肝癌,亟需新疗法。FLC的主要驱动因素是融合肿瘤蛋白DNAJ-PKAc,而针对该蛋白的治疗仍具有挑战性。因此,扩大对 FLC 分子图谱的了解以确定可用于治疗的途径/靶点至关重要。在这里,我们对 FLC 进行了最全面的蛋白质代谢组学综合分析。我们还对患者的 FLC 肿瘤组织切片进行了营养操纵、呼吸测定分析以及关键功能缺失测定。我们提出了一个 FLC 细胞能量学模型,指出脯氨酸合成代谢是由鸟氨酸氨基转移酶活性过高和鸟氨酸转氨酶活性过低介导的,而丝氨酸和谷氨酰胺分解代谢为这一过程提供了燃料。我们强调了 FLC 对电压依赖性阴离子通道(VDAC)的潜在依赖性,VDAC 是线粒体阴离子(包括丙酮酸)的看门人。我们在模型中提出的 FLC 代谢重新布线(重点是线粒体)可被用于寻找治疗漏洞。
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Proteo-metabolomics and patient tumor slice experiments point to amino acid centrality for rewired mitochondria in fibrolamellar carcinoma.

Fibrolamellar carcinoma (FLC) is a rare, lethal, early-onset liver cancer with a critical need for new therapeutics. The primary driver in FLC is the fusion oncoprotein, DNAJ-PKAc, which remains challenging to target therapeutically. It is critical, therefore, to expand understanding of the FLC molecular landscape to identify druggable pathways/targets. Here, we perform the most comprehensive integrative proteo-metabolomic analysis of FLC. We also conduct nutrient manipulation, respirometry analyses, as well as key loss-of-function assays in FLC tumor tissue slices from patients. We propose a model of cellular energetics in FLC pointing to proline anabolism being mediated by ornithine aminotransferase hyperactivity and ornithine transcarbamylase hypoactivity with serine and glutamine catabolism fueling the process. We highlight FLC's potential dependency on voltage-dependent anion channel (VDAC), a mitochondrial gatekeeper for anions including pyruvate. The metabolic rewiring in FLC that we propose in our model, with an emphasis on mitochondria, can be exploited for therapeutic vulnerabilities.

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来源期刊
Cell Reports Medicine
Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)
CiteScore
15.00
自引率
1.40%
发文量
231
审稿时长
40 days
期刊介绍: Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.
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