Generation and Profiling of Tumor-Homing Induced Neural Stem Cells from the Skin of Cancer Patients
Generation and Profiling of Tumor-Homing Induced Neural Stem Cells from the Skin of Cancer Patients
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DOI：
10.1016/j.ymthe.2020.04.022
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发表时间：
2020-07-08
影响因子：
12.4
通讯作者：
Hingtgen, Shawn D.
中科院分区：
文献类型：
--
作者：
Buckley, Andrew;Hagler, Shaye B.;Hingtgen, Shawn D.
将人成纤维细胞转化为个性化诱导的神经干细胞(INSCs)，可以主动寻找肿瘤并输送细胞毒剂，是治疗各种类型癌症的一种非常有前途的方法。然而，从癌症患者的皮肤中产生iNSCs的能力还没有被探索。在这里，我们向临床应用迈出了重要的一步，从正在接受侵袭性脑癌胶质母细胞瘤(GBM)治疗的人类患者的皮肤活检组织中分离出iNSCs。然后，我们利用一组功能和基因组研究来调查这些患者来源的细胞的有效性和肿瘤归巢能力，以及基因组分析，以表征患者之间的差异对这种个性化细胞治疗的影响。从皮肤组织活检中，我们建立了成纤维细胞，并将这些细胞转化为iNSCs。基因组和功能测试显示，在成纤维细胞向iNSC转化的过程中，患者系之间的生长速度、治疗剂生产和基因表达存在显著差异。体内测试显示，患者来源的iNSCs是肿瘤的家园，但归巢相关通路的比率和表达因患者而异。通过使用手术切除的侵袭性人类分化簇133(+)(CD133(+))GBM细胞模型和一系列动态成像，我们发现“高性能”的患者来源的iNSC系将GBM细胞的体积减少了60倍，并将存活时间从28天延长到45天。“低效能”患者系的治疗对肿瘤生长的影响很小，但通过增加腔内剂量可以挽救抗肿瘤的作用。总之，这些数据首次表明，肿瘤归巢的iNSCs可以从癌症患者的皮肤中产生，并有效地抑制肿瘤的生长。我们还开始定义可用于识别细胞的遗传标记，这些细胞将包含对人类患者的肿瘤归巢和杀伤最有效的属性，包括信号素-3B(SEMA3B)的高基因表达，已知该基因参与神经细胞的迁移。这些研究应该成为临床GBM治疗的重要指南，优化的iNSC治疗的个性化本质具有避免移植排斥反应和最大限度地提高治疗耐受性的潜力。
The conversion of human fibroblasts into personalized induced neural stem cells (iNSCs) that actively seek out tumors and deliver cytotoxic agents is a highly promising approach for treating various types of cancer. However, the ability to generate iNSCs from the skin of cancer patients has not been explored. Here, we take an important step toward clinical application by generating iNSCs from skin biopsies of human patients undergoing treatment for the aggressive brain cancer, glioblastoma (GBM). We then utilized a panel of functional and genomic studies to investigate the efficacy and tumor-homing capacity of these patient-derived cells, as well as genomic analysis, to characterize the impact of interpatient variability on this personalized cell therapy. From the skin-tissue biopsies, we established fibroblasts and transdifferentiated the cells into iNSCs. Genomic and functional testing revealed marked variability in growth rates, therapeutic agent production, and gene expression during fibroblast-to-iNSC conversion among patient lines. In vivo testing showed patient-derived iNSCs home to tumors, yet rates and expression of homing-related pathways varied among patients. With the use of surgical-resection mouse models of invasive human cluster of differentiation 133(+) (CD133(+)) GBM cells and serial kinetic imaging, we found that "high-performing" patient-derived iNSC lines reduced the volume of GBM cells 60-fold and extended survival from 28 to 45 days. Treatment with "low-performing" patient lines had minimal effect on tumor growth, but the anti-tumor effect could be rescued by increasing the intracavity dose. Together, these data show, for the first time, that tumor-homing iNSCs can be generated from the skin of cancer patients and efficaciously suppress tumor growth. We also begin to define genetic markers that could be used to identify cells that will contain the most effective attributes for tumor homing and kill in human patients, including high gene expression of the semaphorin-3B (SEMA3B), which is known to be involved in neuronal cell migration. These studies should serve as an important guide toward clinical GBM therapy, where the personalized nature of optimized iNSC therapy has the potential to avoid transplant rejection and maximize treatment durability.