研究动态
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基质刚度触发肿瘤和基质细胞之间的脂质代谢相互作用,介导结肠癌肝转移对贝伐单抗的抗药性。

Matrix stiffness triggers lipid metabolic crosstalk between tumor and stromal cells to mediate bevacizumab resistance in colorectal cancer liver metastases.

发表日期:2023 Aug 23
作者: Yannan Zheng, Rui Zhou, Jianan Cai, Nanyan Yang, Zhaowei Wen, Zhihua Zhang, Huiying Sun, Genjie Huang, Yijin Guan, Na Huang, Min Shi, Yulin Liao, Jianping Bin, Wangjun Liao
来源: CANCER RESEARCH

摘要:

贝伐单抗是一种抗血管内皮生长因子(VEGF)的单克隆抗体,对晚期结直肠癌(CRC)的联合治疗起着重要作用。然而,抵抗力仍然是限制贝伐单抗疗效的主要障碍,突显出识别抗血管生成疗法抵抗机制的重要性。本研究对与代谢过程和对贝伐单抗获得抵抗性相关的细胞外基质(ECM)生物物理性质进行了调查。对接受贝伐单抗联合治疗的20例CRC患者的肝转移前后治疗样本进行了评估,包括10例对治疗反应良好和10例对治疗反应不佳。结果表明,与对治疗反应良好的患者相比,对抗血管生成疗法不佳的患者的肝转移病灶中ECM沉积和高度激活的脂肪酸氧化(FAO)通路均升高。在小鼠肝转移CRC模型中,抗VEGF增加了CRC细胞中的ECM沉积和FAO,而FAO抑制剂etomoxir的治疗增强了抗血管生成疗法的疗效。肝星状细胞(HSCs)对结肠癌细胞中的基质刚度介导的FAO至关重要。基质刚度通过聚焦粘附激酶(FAK)/是的相关蛋白(YAP)通路激活了HSCs中的脂解作用,并且由HSCs分泌的游离脂肪酸被吸收为代谢底物,并激活结肠癌细胞中的FAO。通过FAK和YAP抑制抑制HSC脂解作用可以增强抗VEGF疗法的疗效。综上所述,这些结果表明贝伐单抗诱导的ECM重塑触发了结肠癌细胞与HSCs之间的脂质代谢相互作用。这种受肿瘤微环境调控的贝伐单抗抵抗性的代谢机制代表了逆转药物抵抗性的潜在治疗靶点。
Bevacizumab is an anti-vascular endothelial growth factor (VEGF) monoclonal antibody that plays an important role in the combination treatment of advanced colorectal cancer (CRC). However, resistance remains a major hurdle limiting bevacizumab efficacy, highlighting the importance of identifying mechanism of anti-angiogenic therapy resistance. Here, we investigated biophysical properties of the extracellular matrix (ECM) related to metabolic processes and acquired resistance to bevacizumab. Evaluation of paired pre- and post-treatment samples of liver metastases from 20 CRC patients treated with combination bevacizumab therapy, including 10 responders and 10 non-responders, indicated that ECM deposition in liver metastases and a highly activated fatty acid oxidation (FAO) pathway were elevated in non-responders after anti-angiogenic therapy compared to responders. In mouse models of liver metastatic CRC, anti-VEGF increased ECM deposition and FAO in CRC cells, and treatment with the FAO inhibitor etomoxir enhanced the efficacy of antiangiogenic therapy. Hepatic stellate cells (HSCs) were essential for matrix stiffness-mediated FAO in colon cancer cells. Matrix stiffness activated lipolysis in HSCs via the focal adhesion kinase (FAK)/yes-associated protein (YAP) pathway, and free fatty acids secreted by HSCs were absorbed as metabolic substrates and activated FAO in colon cancer cells. Suppressing HSC lipolysis using FAK and YAP inhibition enhanced the efficacy of anti-VEGF therapy. Together, these results indicate that bevacizumab-induced ECM remodeling triggers lipid metabolic crosstalk between colon cancer cells and HSCs. This metabolic mechanism of bevacizumab resistance mediated by the physical tumor microenvironment represents a potential therapeutic target for reversing drug resistance.