Brain metastasis-associated cancer fibroblasts drive tumor progression and therapeutic resistance through IL26 and CX3CL1 signaling in non-small-cell lung cancer.

IF 13.5 1区 医学 Q1 HEMATOLOGY
S M Abdus Salam, Eshrat Jahan, Eun-Jung Ahn, Sung Sun Kim, Yeong Jin Kim, Sue Jee Park, Tae-Young Jung, In-Young Kim, Shin Jung, Roo Ji Lee, Jae-Hyuk Lee, Joon Haeng Rhee, Kyung Keun Kim, Min-Hee Yi, Kyung-Hwa Lee, Kyung-Sub Moon
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引用次数: 0

Abstract

Brain metastases (BM) from non-small cell lung cancer (NSCLC) represent a significant clinical challenge, characterized by poor prognosis and treatment resistance. While cancer-associated fibroblasts (CAFs) are recognized as crucial components of the BM tumor microenvironment (TME), their mechanistic contributions to disease progression and therapeutic resistance remain poorly understood. In this study, we demonstrated that patient-derived BM-CAFs significantly enhanced NSCLC cell proliferation, migration, invasion and therapeutic resistance in vitro. Mechanistically, BM-CAFs promoted epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) phenotypes through upregulation of key transcription factors. In-vivo experiments showed that co-injection of NSCLC cells with BM-CAFs accelerated tumor growth and enhanced cisplatin resistance. Molecular analysis revealed these effects were mediated through distinct mechanisms whereby IL26 activated the JAK-STAT3 pathway, while CX3CL1 activated both JAK-STAT3 and AKT-mTOR pathways. Importantly, neutralizing antibodies against IL26 and CX3CL1 effectively suppressed their respective signaling pathways and reversed EMT and CSC characteristics. In summary, our findings establish the IL26 and CX3CL1 signaling as a critical mediator of BM-CAF-induced tumor progression and therapy resistance in NSCLC BM, suggesting a potential therapeutic strategy for this challenging disease.

在非小细胞肺癌中,脑转移相关的癌症成纤维细胞通过IL26和CX3CL1信号驱动肿瘤进展和治疗耐药。
非小细胞肺癌(NSCLC)脑转移(BM)是一个重大的临床挑战,其特点是预后差和治疗耐药。虽然癌症相关成纤维细胞(CAFs)被认为是BM肿瘤微环境(TME)的关键组成部分,但它们对疾病进展和治疗耐药性的机制贡献仍然知之甚少。在这项研究中,我们证明了患者来源的BM-CAFs在体外显著增强了NSCLC细胞的增殖、迁移、侵袭和治疗耐药性。在机制上,BM-CAFs通过上调关键转录因子促进上皮-间质转化(EMT)和癌症干细胞(CSC)表型。体内实验表明,NSCLC细胞与BM-CAFs共注射可加速肿瘤生长,增强顺铂耐药性。分子分析显示,这些作用是通过不同的机制介导的,其中IL26激活了JAK-STAT3通路,而CX3CL1激活了JAK-STAT3和AKT-mTOR通路。重要的是,针对IL26和CX3CL1的中和抗体有效地抑制了它们各自的信号通路,逆转了EMT和CSC的特征。总之,我们的研究结果表明,IL26和CX3CL1信号是BM- cafa诱导的非小细胞肺癌肿瘤进展和治疗耐药的关键介质,为这种具有挑战性的疾病提供了潜在的治疗策略。
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来源期刊
CiteScore
12.60
自引率
7.30%
发文量
97
审稿时长
6 weeks
期刊介绍: Experimental Hematology & Oncology is an open access journal that encompasses all aspects of hematology and oncology with an emphasis on preclinical, basic, patient-oriented and translational research. The journal acts as an international platform for sharing laboratory findings in these areas and makes a deliberate effort to publish clinical trials with 'negative' results and basic science studies with provocative findings. Experimental Hematology & Oncology publishes original work, hypothesis, commentaries and timely reviews. With open access and rapid turnaround time from submission to publication, the journal strives to be a hub for disseminating new knowledge and discussing controversial topics for both basic scientists and busy clinicians in the closely related fields of hematology and oncology.
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