Cancer-associated fibroblast derived CXCL14 drives cisplatin chemoresistance by enhancing nucleotide excision repair in bladder cancer.

IF 12.8 1区 医学 Q1 ONCOLOGY
Tinghao Li, Kunyao Zhu, Hang Tong, Yan Sun, Junlong Zhu, Zijia Qin, Junrui Chen, Linfeng Wu, Xiaoyu Zhang, Aimin Wang, Xin Gou, Hubin Yin, Weiyang He
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引用次数: 0

Abstract

Background: A significant challenge in bladder cancer treatment is primary chemoresistance, in which cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) play a pivotal role. While the contributions of CAFs to tumor progression and drug resistance are well established, the precise molecular mechanisms by which they induce chemoresistance remain unclear. A comprehensive understanding of the effect of TME modulation-particularly through CAFs-on the chemotherapeutic response is crucial for developing effective strategies to overcome chemoresistance and improve patient survival.

Methods: Primary fibroblasts were isolated from paired clinical samples of bladder cancer tissues and adjacent normal tissues to identify key CAF-derived secretory factors. Bioinformatics analysis, semiquantitative RT‒qPCR, and dual-luciferase reporter assays were subsequently used to investigate the functional role and mechanistic basis of CXCL14 in chemoresistance. The therapeutic relevance of these findings was further evaluated through in vitro and in vivo models, including ex vivo patient-derived organoid (PDO) models, by assessing cisplatin sensitivity and validating therapeutic targeting of the CXCL14-CCR7-STAT3 axis with small molecule inhibitors.

Results: Compared to normal fibroblasts and CAFs from nonchemoresistance groups, CAFs derived from cisplatin-resistant patients demonstrated significantly greater paracrine-mediated induction of chemoresistance. Mechanistically, CAF-secreted CXCL14 engaged CCR7 on bladder cancer cells, triggering STAT3 phosphorylation and consequently upregulating the DNA repair gene ERCC4 to promote cisplatin resistance. In vivo validation confirmed that pharmacological CCR7 or STAT3 inhibition markedly reversed chemoresistance and potentiated cisplatin-induced tumor cell death. Notably, STAT3 activation mediated the overexpression of the glycolytic enzymes HK2 and LDHA, resulting in greater glycolytic flux in resistant cells. This metabolic reprogramming further facilitated the transdifferentiation of normal fibroblasts into CXCL14-secreting CAFs, establishing a self-reinforcing feedback loop that sustains chemoresistance.

Conclusion: The CXCL14/CCR7/STAT3 axis critically mediates cisplatin resistance in bladder cancer through dual modulation of DNA repair and glycolytic metabolism. Therapeutic cotargeting of this pathway with CCR7 or STAT3 inhibitors combined with cisplatin represents a promising strategy to overcome chemoresistance and improve clinical outcomes.

癌症相关成纤维细胞衍生的CXCL14通过增强膀胱癌的核苷酸切除修复驱动顺铂化疗耐药。
背景:原发性化疗耐药是膀胱癌治疗的一个重大挑战,其中肿瘤微环境(TME)中的癌症相关成纤维细胞(CAFs)起着关键作用。虽然CAFs对肿瘤进展和耐药的贡献已经确定,但它们诱导化疗耐药的确切分子机制仍不清楚。全面了解TME调节(特别是通过cafs)对化疗反应的影响对于制定克服化疗耐药和提高患者生存率的有效策略至关重要。方法:从配对的膀胱癌组织和邻近正常组织中分离原代成纤维细胞,鉴定关键的caf衍生分泌因子。随后采用生物信息学分析、半定量RT-qPCR和双荧光素酶报告基因分析来研究CXCL14在化学耐药中的功能作用和机制基础。通过体外和体内模型,包括体外患者源性类器官(PDO)模型,通过评估顺铂敏感性和验证小分子抑制剂对CXCL14-CCR7-STAT3轴的治疗靶向性,进一步评估这些发现的治疗相关性。结果:与正常成纤维细胞和来自非化疗耐药组的CAFs相比,来自顺铂耐药患者的CAFs表现出更大的旁分泌介导的化疗耐药诱导。从机制上讲,caf分泌的CXCL14与膀胱癌细胞上的CCR7结合,触发STAT3磷酸化,从而上调DNA修复基因ERCC4,促进顺铂耐药。体内验证证实,药理学CCR7或STAT3抑制可显著逆转化疗耐药并增强顺铂诱导的肿瘤细胞死亡。值得注意的是,STAT3激活介导糖酵解酶HK2和LDHA的过表达,导致抗性细胞中糖酵解通量增大。这种代谢重编程进一步促进了正常成纤维细胞向分泌cxcl14的CAFs的转分化,建立了一个自我强化的反馈回路,维持了化疗耐药。结论:CXCL14/CCR7/STAT3轴通过DNA修复和糖酵解代谢的双重调节,在膀胱癌顺铂耐药中起关键作用。将该途径与CCR7或STAT3抑制剂联合顺铂进行治疗共靶向是克服化疗耐药和改善临床结果的有希望的策略。
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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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