Wellman Center for Photomedicine, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Wellman Center for Photomedicine, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; The University of Texas School of Medicine, San Antonio, TX, USA.
Biomaterials. 2019 Nov;222:119421. doi: 10.1016/j.biomaterials.2019.119421. Epub 2019 Aug 12.
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 mitochondrial 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.
癌细胞与其微环境之间的复杂相互作用仍然是设计和优化胰腺导管腺癌 (PDAC) 治疗策略的主要挑战。最近的研究表明，机制上不同的联合治疗方法有望治疗 PDAC，但有效的临床转化需要更准确的模型，该模型要考虑到丰富的肿瘤基质及其对癌症生长、代谢和治疗不敏感性的影响。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 赋予了奥沙利铂化疗和苯并卟啉衍生物介导的光动力疗法显著且具有统计学意义的耐药性，这与基础氧化代谢水平的升高有关。在 PDAC 的原位异种移植模型中也观察到类似的治疗抵抗性和氧化还原状态增加，其中在小鼠中共同植入了癌细胞和 CAF。奥沙利铂和 PDT 与线粒体复合物 I 抑制剂二甲双胍联合治疗克服了 CAF 诱导的治疗抵抗。这些发现强调了异质微肿瘤培养模型可再现源自肿瘤基质相互作用的代谢改变。所提出的基础设施可以与特定疾病的细胞类型相适应，并与患者来源的组织兼容，以实现针对胰腺癌的个性化筛选和优化新的代谢靶向治疗方案。
