Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France; COMPO unit, Inria Sophia Antipolis and CRCM, INSERM U1068, CNRS UMR7258, Aix-Marseille Université UM105, Marseille, France.
Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France.
EBioMedicine. 2021 Apr;66:103332. doi: 10.1016/j.ebiom.2021.103332. Epub 2021 Apr 13.
Although significant advances have been made recently to characterize the biology of pancreatic ductal adenocarcinoma (PDAC), more efforts are needed to improve our understanding and to face challenges related to the aggressiveness, high mortality rate and chemoresistance of this disease.
In this study, we perform the metabolomics profiling of 77 PDAC patient-derived tumor xenografts (PDTX) to investigate the relationship of metabolic profiles with overall survival (OS) in PDAC patients, tumor phenotypes and resistance to five anticancer drugs (gemcitabine, oxaliplatin, docetaxel, SN-38 and 5-Fluorouracil).
We identified a metabolic signature that was able to predict the clinical outcome of PDAC patients (p < 0.001, HR=2.68 [95% CI: 1.5-4.9]). The correlation analysis showed that this metabolomic signature was significantly correlated with the PDAC molecular gradient (PAMG) (R = 0.44 and p < 0.001) indicating significant association to the transcriptomic phenotypes of tumors. Resistance score established, based on growth rate inhibition metrics using 35 PDTX-derived primary cells, allowed to identify several metabolites related to drug resistance which was globally accompanied by accumulation of several diacy-phospholipids and decrease in lysophospholipids. Interestingly, targeting glycerophospholipid synthesis improved sensitivity to the three tested cytotoxic drugs indicating that interfering with metabolism could be a promising therapeutic strategy to overcome the challenging resistance of PDAC.
In conclusion, this study shows that the metabolomic profile of pancreatic PDTX models is strongly associated to clinical outcome, transcriptomic phenotypes and drug resistance. We also showed that targeting the lipidomic profile could be used in combinatory therapies against chemoresistance in PDAC.
尽管最近在描述胰腺导管腺癌（PDAC）的生物学方面取得了重大进展，但仍需要更多的努力来提高我们的认识，并应对该疾病侵袭性强、死亡率高和化疗耐药的挑战。
在这项研究中，我们对 77 例 PDAC 患者衍生肿瘤异种移植（PDTX）进行代谢组学分析，以研究代谢谱与 PDAC 患者总生存期（OS）、肿瘤表型和对五种抗癌药物（吉西他滨、奥沙利铂、多西他赛、SN-38 和 5-氟尿嘧啶）的耐药性之间的关系。
我们确定了一个能够预测 PDAC 患者临床结局的代谢特征（p<0.001，HR=2.68[95%CI：1.5-4.9]）。相关性分析表明，该代谢组学特征与 PDAC 分子梯度（PAMG）显著相关（R=0.44，p<0.001），表明与肿瘤的转录组表型有显著关联。基于使用 35 个 PDTX 衍生的原代细胞的生长抑制率指标建立的耐药评分，确定了与耐药性相关的几种代谢物，这与几种二酰基磷脂的积累和溶血磷脂的减少相一致。有趣的是，靶向甘油磷脂合成可提高对三种测试细胞毒药物的敏感性，这表明干扰代谢可能是克服 PDAC 挑战性耐药性的一种有前途的治疗策略。
综上所述，这项研究表明胰腺 PDTX 模型的代谢组学特征与临床结局、转录组表型和耐药性密切相关。我们还表明，靶向脂质组学特征可用于联合治疗 PDAC 的化疗耐药性。
