外泌体包裹的来自癌症相关成纤维细胞的环状 BIRC6 通过 SUMOylation 修饰在胰腺癌中诱导铂耐药性。
Extracellular vesicle-packaged circBIRC6 from cancer-associated fibroblasts induce platinum resistance via SUMOylation modulation in pancreatic cancer.
机构信息
Department of Pancreas Center, Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, 510080, Guangdong, China.
School of medicine, South China University of Technology, Guangzhou, 510006, Guangdong Province, China.
出版信息
J Exp Clin Cancer Res. 2023 Nov 28;42(1):324. doi: 10.1186/s13046-023-02854-3.
BACKGROUND
Cancer-associated fibroblasts (CAFs) play pivotal roles in chemoresistance of pancreatic ductal adenocarcinoma (PDAC). However, the underlying mechanisms are poorly understood. Revealing the cross-talk network between tumor stroma and pancreatic cancer and developing effective strategies against oxaliplatin resistance are highly desired in the clinic.
METHODS
High-throughput sequence was used to screened the key circRNAs transmitted by extracellular vesicles (EVs) from CAFs to pancreatic cancer cells. The associations between EV-packaged circBIRC6 and chemotherapy responsiveness were validated in a cohort of 82 cases of advanced PDAC patients. Then, the effects of EV-packaged circBIRC6 on CAF-induced oxaliplatin resistance were investigated by flow cytometry, colony formation, viability of pancreatic cancer organoids in vitro and by xenograft models in vivo. RNA pulldown, RNA immunoprecipitation, and sites mutation assays were used to reveal the underlying mechanism.
RESULTS
We identified a circRNA, circBIRC6, is significantly upregulated in CAF-derived EVs and is positively associated with oxaliplatin-based chemoresistance. In vitro and in vivo functional assays showed that CAF-derived EV-packaged circBIRC6 enhance oxaliplatin resistance of pancreatic cancer cells and organoids via regulating the non-homologous end joining (NHEJ) dependent DNA repair. Mechanistically, circBIRC6 directly binds with XRCC4 and enhanced the interaction of XRCC4 with SUMO1 at the lysine 115 residue, which facilitated XRCC4 chromatin localization. XRCC4 mutation dramatically abrogated the EV-packaged circBIRC6 induced effect. Moreover, combination of antisense oligonucleotide inhibitors against circBIRC6 with Olaparib dramatically suppressed chemoresistance in patient-derived xenograft models.
CONCLUSIONS
Our study revealed that EV-packaged circBIRC6 confer oxaliplatin resistance in PDAC by mediating SUMOylation of XRCC4, introducing a promising predictive and therapeutic target for PDAC on oxaliplatin resistance.
背景
癌症相关成纤维细胞（CAFs）在胰腺导管腺癌（PDAC）的化疗耐药中起关键作用。然而，其潜在机制尚不清楚。在临床上，揭示肿瘤基质与胰腺癌之间的串扰网络并开发针对奥沙利铂耐药的有效策略是非常需要的。
方法
使用高通量测序筛选来自 CAF 的细胞外囊泡（EVs）传递给胰腺癌细胞的关键 circRNAs。在 82 例晚期 PDAC 患者的队列中验证了 EV 包裹的 circBIRC6 与化疗反应性之间的关联。然后，通过流式细胞术、集落形成、体外胰腺癌细胞类器官活力以及体内异种移植模型研究 EV 包裹的 circBIRC6 对 CAF 诱导的奥沙利铂耐药的影响。使用 RNA 下拉、RNA 免疫沉淀和位点突变测定来揭示潜在的机制。
结果
我们鉴定出一种 circRNA，circBIRC6，在 CAF 衍生的 EV 中显著上调，并与基于奥沙利铂的化疗耐药性呈正相关。体外和体内功能测定表明，CAF 衍生的 EV 包裹的 circBIRC6 通过调节非同源末端连接（NHEJ）依赖性 DNA 修复增强胰腺癌细胞和类器官对奥沙利铂的耐药性。机制上，circBIRC6 直接与 XRCC4 结合，并增强 XRCC4 与 SUMO1 在赖氨酸 115 残基上的相互作用，从而促进 XRCC4 染色质定位。XRCC4 突变显著消除了 EV 包裹的 circBIRC6 诱导的作用。此外，针对 circBIRC6 的反义寡核苷酸抑制剂与奥拉帕利联合使用可显著抑制患者来源的异种移植模型中的化疗耐药性。
结论
我们的研究表明，EV 包裹的 circBIRC6 通过介导 XRCC4 的 SUMO 化赋予 PDAC 奥沙利铂耐药性，为 PDAC 的奥沙利铂耐药性提供了有前途的预测和治疗靶点。
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