A Localized Chimeric Hydrogel Therapy Combats Tumor Progression through Alteration of Sphingolipid Metabolism

Rapid
proliferation of cancer cells assisted by endothelial cell-mediated
angiogenesis and acquired inflammation at the tumor microenvironment
(TME) lowers the success rate of chemotherapeutic regimens. Therefore,
targeting these processes using localized delivery of a minimally
toxic drug combination may be a promising strategy. Here, we present
engineering of a biocompatible self-assembled lithocholic acid-dipeptide
derived hydrogel (TRI-Gel) that can maintain sustained delivery of
antiproliferating doxorubicin, antiangiogenic combretastatin-A4 and
anti-inflammatory dexamethasone. Application of TRI-Gel therapy to
a murine tumor model promotes enhanced apoptosis with a concurrent
reduction in angiogenesis and inflammation, leading to effective abrogation
of tumor proliferation and increased median survival with reduced
drug resistance. In-depth RNA-sequencing analysis showed that TRI-Gel
therapy induced transcriptome-wide alternative splicing of many genes
responsible for oncogenic transformation including sphingolipid genes.
We demonstrate that TRI-Gel therapy targets the reversal of a unique
intron retention event in β-glucocerebrosidase 1 (Gba1), thereby increasing the availability of functional Gba1 protein.
An enhanced Gba1 activity elevates ceramide levels responsible for
apoptosis and decreases glucosylceramides to overcome drug resistance.
Therefore, TRI-Gel therapy provides a unique system that affects the
TME via post-transcriptional modulations of sphingolipid metabolic
genes, thereby opening a new and rational approach to cancer therapy.

内皮细胞介导的血管生成与肿瘤微环境（tumor microenvironment, TME）中获得性炎症所辅助的癌细胞快速增殖，会降低化疗方案的成功率。因此，采用局部递送低毒性药物组合的方式靶向上述病理过程，不失为一种颇具前景的治疗策略。本研究构建了一种生物相容性自组装石胆酸-二肽衍生水凝胶（TRI-Gel），可实现抗增殖药物多柔比星（doxorubicin）、抗血管生成药物康普瑞汀-A4（combretastatin-A4）以及抗炎药物地塞米松（dexamethasone）的持续缓释。将TRI-Gel疗法应用于小鼠肿瘤模型，可显著促进肿瘤细胞凋亡，同时抑制血管生成与炎症反应，有效阻断肿瘤增殖，延长小鼠中位生存期并降低药物耐药性。深入的RNA测序（RNA-sequencing）分析显示，TRI-Gel疗法可诱导与肿瘤转化相关的诸多基因（包括鞘脂代谢基因）发生全转录组范围的可变剪接。本研究证实，TRI-Gel疗法可靶向逆转β-葡萄糖脑苷脂酶1（β-glucocerebrosidase 1, Gba1）中独特的内含子保留事件，从而提升功能性Gba1蛋白的表达量。增强的Gba1活性可升高介导细胞凋亡的神经酰胺（ceramide）水平，并降低葡糖基神经酰胺（glucosylceramides）含量，以此克服药物耐药性。综上，TRI-Gel疗法通过对鞘脂代谢基因进行转录后调控来重塑肿瘤微环境，为癌症治疗提供了一种全新的理性化策略。