Wu Chuntao, Hu Beiyuan, Wang Lei, Wu Xia, Gu Haitao, Dong Hanguang, Yan Jiuliang, Qi Zihao, Zhang Qi, Chen Huan, Yu Bo, Hu Sheng, Qian Yu, Dong Shuang, Li Qiang, Wang Xu, Long Jiang
Department of Pancreatic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
iScience. 2022 Dec 5;26(1):105723. doi: 10.1016/j.isci.2022.105723. eCollection 2023 Jan 20.
Lipid metabolism is extensively reprogrammed in pancreatic ductal adenocarcinoma (PDAC). Stearoyl-coenzyme A desaturase (SCD) is a critical lipid regulator that was unexplored in PDAC. Here, we characterized the existence of cancer-associated fibroblasts (CAFs) with high SCD expression, and revealed them as an unfavorable prognostic factor. Therefore, primary CAFs and pancreatic cancer cells were harvested and genetically labeled. The mixture of CAFs and cancer cells were co-injected into scd; prkdc, or hIGF1/INS-expressing zebrafish to generate patient-derived xenograft models (zPDX). The models were aligned in 3D-printed chips for semi-automatic drug administration and high-throughput scanning. The results showed that chaperoning of the SCD-high CAFs significantly improved the drug resistance of pancreatic cancer cells against gemcitabine and cisplatin, while the administration of SCD inhibitors neutralized the protective effect. Our studies revealed the prognostic and therapeutic value of stromal SCD in PDAC, and proposed the application of zPDX model chips for drug testing.
脂质代谢在胰腺导管腺癌（PDAC）中被广泛重编程。硬脂酰辅酶A去饱和酶（SCD）是一种关键的脂质调节因子，在PDAC中尚未得到研究。在这里，我们鉴定了具有高SCD表达的癌症相关成纤维细胞（CAF）的存在，并揭示它们是一个不良预后因素。因此，收集原代CAF和胰腺癌细胞并进行基因标记。将CAF和癌细胞的混合物共注射到表达scd、prkdc或hIGF1/INS的斑马鱼中，以生成患者来源的异种移植模型（zPDX）。将模型排列在3D打印芯片中，用于半自动给药和高通量扫描。结果表明，SCD高表达的CAF的陪伴显著提高了胰腺癌细胞对吉西他滨和顺铂的耐药性，而给予SCD抑制剂可中和这种保护作用。我们的研究揭示了基质SCD在PDAC中的预后和治疗价值，并提出了zPDX模型芯片在药物测试中的应用。
