Modulation of redox metabolism negates cancer-associated fibroblasts induced treatment resistance in a heterotypic 3D culture platform of pancreatic cancer
Modulation of redox metabolism negates cancer-associated fibroblasts induced treatment resistance in a heterotypic 3D culture platform of pancreatic cancer
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DOI：
10.1016/j.biomaterials.2019.119421
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发表时间：
2019-11-01
期刊：
影响因子：
14
通讯作者：
Hasan, Tayyaba
中科院分区：
文献类型：
--
作者：
Broekgaarden, Mans;Anbil, Sriram;Hasan, Tayyaba
癌细胞与其微环境之间复杂的相互作用仍然是胰腺导管腺癌（PDAC）治疗策略设计和优化的主要挑战。最近的研究表明，机制上不同的联合疗法有望治疗 PDAC，但有效的临床转化需要更准确的模型来解释丰富的肿瘤基质及其对癌症生长、代谢和治疗不敏感的影响。在这项研究中，开发了一种由 PDAC 细胞和患者来源的癌症相关成纤维细胞 (CAF) 组成的模块化 3D 培养模型，以评估 PDAC-CAF 相互作用对治疗效果的影响。使用新开发的高通量成像和图像分析工具，发现 CAF 对奥沙利铂化疗和苯并卟啉衍生物介导的光动力疗法具有显着且具有统计学意义的抵抗力，这与基础氧化代谢水平的增加有关。在将癌细胞和 CAF 共同植入小鼠体内的 PDAC 原位异种移植模型中，同样观察到了治疗抵抗力和氧化还原状态的增加。奥沙利铂和 PDT 与线粒体复合物 I 抑制剂二甲双胍的联合治疗克服了 CAF 诱导的治疗耐药性。研究结果强调，异型微肿瘤培养模型概括了肿瘤-基质相互作用引起的代谢变化。所提出的基础设施可以适应疾病特异性细胞类型，并与患者来源的组织兼容，从而能够对胰腺癌新的代谢靶向治疗方案进行个性化筛选和优化。
The complex interplay between cancer cells and their microenvironment remains a major challenge in the design and optimization of treatment strategies for pancreatic ductal adenocarcinoma (PDAC). Recent investigations have demonstrated that mechanistically distinct combination therapies hold promise for treatment of PDAC, but effective clinical translation requires more accurate models that account for the abundant tumor-stroma and its influence on cancer growth, metabolism and treatment insensitivity. In this study, a modular 3D culture model that comprised PDAC cells and patient-derived cancer-associated fibroblasts (CAFs) was developed to assess the effects of PDAC-CAF interactions on treatment efficacies. Using newly-developed high-throughput imaging and image analysis tools, it was found that CAFs imparted a notable and statistically significant resistance to oxaliplatin chemotherapy and benzoporphyrin derivative-mediated photodynamic therapy, which associated with increased levels of basal oxidative metabolism. Increased treatment resistance and redox states were similarly observed in an orthotopic xenograft model of PDAC in which cancer cells and CAFs were co-implanted in mice. Combination therapies of oxaliplatin and PDT with the mitochondria] complex I inhibitor metformin overcame CAF-induced treatment resistance. The findings underscore that heterotypic microtumor culture models recapitulate metabolic alterations stemming from tumor-stroma interactions. The presented infrastructure can be adapted with disease-specific cell types and is compatible with patient-derived tissues to enable personalized screening and optimization of new metabolism-targeted treatment regimens for pancreatic cancer.