Adipocytes-induced ANGPTL4/KLF4 axis drives glycolysis and metastasis in triple-negative breast cancer.

IF 12.8 1区医学 Q1 ONCOLOGY

Journal of Experimental & Clinical Cancer Research Pub Date : 2025-07-04 DOI:10.1186/s13046-025-03458-9

Dou Yin, Nana Fang, Yaling Zhu, Xiaoqing Bao, Juan Yang, Qingyu Zhang, Ruimeng Wang, Jiahui Huang, Qibing Wu, Fang Ma, Xiaohui Wei

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引用次数: 0

Abstract

Background: The adipocyte-rich tumor microenvironment (TME) is recognized as a key factor in promoting cancer progression. A distinct characteristic of peritumoral adipocytes is their reduced lipid content and the acquisition of a proinflammatory phenotype. However, the underlying mechanisms by which adipocytes rewire metabolism and boost tumor progression in triple-negative breast cancer (TNBC) remain poorly understood.

Methods: We utilized transcriptomic analysis, bioinformatic analysis, metabolic flux analysis, protein-protein docking, gene and protein expression profiling, in vivo metastasis analysis and breast cancer specimens to explore how adipocytes reprogram tumor metabolism and progression in TNBC.

Results: Our findings reveal that Angiopoietin-like 4 (ANGPTL4) exhibits significantly higher expression levels in adipocyte-rich tumor circumstance compared to the symbiotic environment lacking of adipocyte. Furthermore, ANGPTL4 expression in tumor cells is essential for adipocyte-driven glycolysis and metastasis. Interleukin 6 (IL-6), enriched in cancer-associated adipocytes, and lipolysis-derived free fatty acids (FFAs) released from adipocytes, amplify ANGPTL4-mediated glycolysis and metastasis through activation of STAT3 and PPARα pathways in TNBC cells. Additionally, ANGPTL4 interacts with transcription factor KLF4 and enhances KLF4 activity, which further drives glycolysis and metastasis, whereas KLF4 knockdown attenuates migration and glycolysis in TNBC cells. Importantly, Elevated ANGPTL4 and KLF4 expression was observed in metastatic breast cancer specimens compared to non-metastatic cases and was positively correlated with poor prognosis.

Conclusion: Collectively, our results uncover a complex metabolic interaction between adipocytes and TNBC cells that promotes tumor aggressiveness. ANGPTL4 emerges as a key mediator in this process, making it a promising therapeutic target to inhibit TNBC progression.

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脂肪细胞诱导的ANGPTL4/KLF4轴驱动三阴性乳腺癌的糖酵解和转移。

背景：富含脂肪细胞的肿瘤微环境（TME）被认为是促进癌症进展的关键因素。肿瘤周围脂肪细胞的一个明显特征是它们的脂质含量降低和获得促炎表型。然而，脂肪细胞重组代谢和促进三阴性乳腺癌（TNBC）肿瘤进展的潜在机制仍然知之甚少。方法：利用转录组学分析、生物信息学分析、代谢通量分析、蛋白对接、基因和蛋白表达谱分析、体内转移分析和乳腺癌标本，探讨TNBC中脂肪细胞如何重编程肿瘤代谢和进展。结果：我们发现血管生成素样4 （ANGPTL4）在富含脂肪细胞的肿瘤环境中表达水平明显高于缺乏脂肪细胞的共生环境。此外，肿瘤细胞中ANGPTL4的表达对于脂肪细胞驱动的糖酵解和转移至关重要。富含癌症相关脂肪细胞的白细胞介素6 （IL-6）和脂肪细胞释放的游离脂肪酸（FFAs）通过激活TNBC细胞中STAT3和PPARα通路，放大angptl4介导的糖酵解和转移。此外，ANGPTL4与转录因子KLF4相互作用，增强KLF4活性，进一步推动糖酵解和转移，而KLF4敲低会减弱TNBC细胞的迁移和糖酵解。重要的是，与非转移病例相比，转移性乳腺癌标本中ANGPTL4和KLF4表达升高，且与预后不良呈正相关。结论：总的来说，我们的研究结果揭示了脂肪细胞和TNBC细胞之间复杂的代谢相互作用，促进了肿瘤的侵袭性。在这一过程中，ANGPTL4作为一个关键的介质出现，使其成为抑制TNBC进展的一个有希望的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Experimental & Clinical Cancer Research 医学-肿瘤学

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.