Domenichini Alice, Edmands Jeanne S, Adamska Aleksandra, Begicevic Romana-Rea, Paternoster Silvano, Falasca Marco
Metabolic Signalling Group, School of Pharmacy & Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, 6102, Australia.
Curtin Health Innovation Research Institute, Curtin University, Perth, WA, 6102, Australia.
Adv Biol Regul. 2019 May;72:63-77. doi: 10.1016/j.jbior.2019.02.001. Epub 2019 Feb 23.
Cancer stem cells are a population of slow-cycling cells within the tumour bulk, with self-renewal capacity that attracts interest as a therapeutic target. In highly heterogeneous tumours, like pancreatic ductal adenocarcinoma (PDAC) however, the characterisation of cancer stem cells has led to controversial results due to the lack of consensus on specific markers. Here we investigated the characteristics of a population of pancreatic cancer tumorspheres derived from different human pancreatic cancer cell lines and a primary line from a genetically engineered KPC mouse model, using flow cytometry and western blotting to analyse surface and stemness markers. We analysed tumorspheres tumorigenic potential using anchorage-independent soft agar assay as well as their metabolic plasticity and chemoresistance. Pancreatic cancer tumorspheres display a heterogeneous pattern of surface and stemness markers, nevertheless they are characterised by an increased tumorigenic potential and higher chemoresistance. In addition, we have shown that pancreatic cancer tumorspheres have a unique metabolic profile with reduced metabolic potential. Together our results indicate that, despite the heterogeneity characterising pancreatic cancer tumorspheres, we can identify a functional vulnerability that represents a window for pharmacological intervention and development of novel therapeutic strategies.
癌症干细胞是肿瘤主体内一群增殖缓慢的细胞，具有自我更新能力，作为治疗靶点备受关注。然而，在高度异质性的肿瘤中，如胰腺导管腺癌（PDAC），由于缺乏关于特定标志物的共识，癌症干细胞的特征鉴定结果存在争议。在此，我们利用流式细胞术和蛋白质免疫印迹法分析表面标志物和干性标志物，研究了源自不同人类胰腺癌细胞系以及基因工程KPC小鼠模型原代细胞系的胰腺癌肿瘤球群体的特征。我们通过非锚定依赖的软琼脂试验分析了肿瘤球的致瘤潜力以及它们的代谢可塑性和化学抗性。胰腺癌肿瘤球表现出表面标志物和干性标志物的异质性模式，但其特征是致瘤潜力增加和化学抗性增强。此外，我们还表明，胰腺癌肿瘤球具有独特的代谢谱，代谢潜力降低。我们的研究结果共同表明，尽管胰腺癌肿瘤球具有异质性，但我们能够识别出一种功能性脆弱性，这代表了药物干预和开发新型治疗策略的一个窗口。
