LMO3 is a suppressor of the basal-like/squamous subtype and reduces disease aggressiveness of pancreatic cancer through glycerol 3-phosphate metabolism.

IF 3.3 3区 医学 Q2 ONCOLOGY
Yuuki Ohara, Amanda J Craig, Huaitian Liu, Shouhui Yang, Paloma Moreno, Tiffany H Dorsey, Helen Cawley, Azadeh Azizian, Jochen Gaedcke, Michael Ghadimi, Nader Hanna, Stefan Ambs, S Perwez Hussain
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引用次数: 0

Abstract

Pancreatic ductal adenocarcinoma (PDAC) encompasses diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, each exhibiting distinct characteristics, with the latter known for its aggressiveness. We employed an integrative approach combining transcriptome and metabolome analyses to pinpoint potential genes contributing to the basal-like/squamous subtype differentiation. Applying this approach to our NCI-UMD-German and a validation cohort, we identified LIM Domain Only 3 (LMO3), a transcription co-factor, as a candidate suppressor of the basal-like/squamous subtype. Reduced LMO3 expression was significantly associated with higher pathological grade, advanced disease stage, induction of the basal-like/squamous subtype and decreased survival among PDAC patients. In vitro experiments demonstrated that LMO3 transgene expression inhibited PDAC cell proliferation and migration/invasion, concurrently downregulating the basal-like/squamous gene signature. Metabolome analysis of patient tumors and PDAC cells revealed a metabolic program linked to elevated LMO3 and the classical/progenitor subtype, characterized by enhanced lipogenesis and suppressed amino acid metabolism. Notably, glycerol 3-phosphate (G3P) levels positively correlated with LMO3 expression and associated with improved patient survival. Furthermore, glycerol-3-phosphate dehydrogenase 1 (GPD1), a crucial enzyme in G3P synthesis, showed upregulation in LMO3-high and classical/progenitor PDAC, suggesting its potential role in mitigating disease aggressiveness. Collectively, our findings suggest that heightened LMO3 expression reduces transcriptome and metabolome characteristics indicative of basal-like/squamous tumors with decreased disease aggressiveness in PDAC patients. The observations describe LMO3 as a candidate for diagnostic and therapeutic targeting in PDAC.

LMO3 是基底样/鳞状亚型的抑制因子,通过甘油-3-磷酸代谢降低胰腺癌的侵袭性。
胰腺导管腺癌(PDAC)包含多种分子亚型,包括经典/原发亚型和基底样/鳞状亚型,每种亚型都表现出不同的特征,其中基底样/鳞状亚型以其侵袭性著称。我们采用了一种结合转录组和代谢组分析的综合方法,以确定导致基底样/鳞状亚型分化的潜在基因。将这种方法应用于我们的 NCI-UMD-German 和一个验证队列,我们发现 LIM Domain Only 3(LMO3)(一种转录辅助因子)是基底样/鳞状亚型的候选抑制因子。LMO3 表达的降低与病理分级升高、疾病分期晚期、基底样/鳞状亚型的诱导以及 PDAC 患者生存率的降低有显著相关性。体外实验表明,LMO3转基因表达抑制了PDAC细胞的增殖和迁移/侵袭,同时下调了基底样/鳞状细胞基因特征。对患者肿瘤和 PDAC 细胞的代谢组分析表明,代谢程序与 LMO3 的升高和经典/原癌基因亚型有关,其特点是脂肪生成增强和氨基酸代谢受抑制。值得注意的是,甘油-3-磷酸(G3P)水平与LMO3的表达呈正相关,并与患者生存率的提高有关。此外,甘油-3-磷酸脱氢酶1(GPD1)是合成G3P的关键酶,在LMO3高表达和经典/原发PDAC中显示出上调,表明其在减轻疾病侵袭性方面的潜在作用。总之,我们的研究结果表明,LMO3表达的增加降低了转录组和代谢组的特征,表明基底样/鳞状肿瘤的特征,降低了PDAC患者疾病的侵袭性。这些观察结果表明,LMO3 是 PDAC 诊断和治疗的候选靶点。
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来源期刊
Carcinogenesis
Carcinogenesis 医学-肿瘤学
CiteScore
9.20
自引率
2.10%
发文量
95
审稿时长
1 months
期刊介绍: Carcinogenesis: Integrative Cancer Research is a multi-disciplinary journal that brings together all the varied aspects of research that will ultimately lead to the prevention of cancer in man. The journal publishes papers that warrant prompt publication in the areas of Biology, Genetics and Epigenetics (including the processes of promotion, progression, signal transduction, apoptosis, genomic instability, growth factors, cell and molecular biology, mutation, DNA repair, genetics, etc.), Cancer Biomarkers and Molecular Epidemiology (including genetic predisposition to cancer, and epidemiology), Inflammation, Microenvironment and Prevention (including molecular dosimetry, chemoprevention, nutrition and cancer, etc.), and Carcinogenesis (including oncogenes and tumor suppressor genes in carcinogenesis, therapy resistance of solid tumors, cancer mouse models, apoptosis and senescence, novel therapeutic targets and cancer drugs).
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