Genetic and microenvironmental evolution of colorectal liver metastases under chemotherapy.

IF 11.7 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2024-12-17 Epub Date: 2024-12-03 DOI:10.1016/j.xcrm.2024.101838

Min Shi, Yingxi Yang, Na Huang, Dongqiang Zeng, Zongchao Mo, Jiao Wang, Xiaomeng Zhang, Ran Liu, Chunlin Wang, Xiaoxiang Rong, Zhenzhen Wu, Qiong Huang, Haixia Shang, Jihong Tang, Zhaojun Wang, Jianan Cai, Genjie Huang, Yijin Guan, Jian Guo, Quanhua Mu, Jiguang Wang, Wangjun Liao

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引用次数: 0

Abstract

Drug resistance limits the efficacy of chemotherapy for colorectal cancer liver metastasis (CRLM). However, the evolution of CRLM during drug treatment remains poorly elucidated. Multi-omics and treatment response data from 115 samples of 49 patients with CRLM undergoing bevacizumab (BVZ)-based chemotherapy show little difference in genomic alterations in 92% of cases, while remarkable differences are observed at the transcriptomic level. By decoupling intrinsic and acquired resistance, we find that hepatocyte and myeloid cell infiltration contribute to 38.5% and 23.1% of acquired resistance, respectively. Importantly, SMAD4 mutations and chr20q copy-number gain are associated with intrinsic chemoresistance. Gene interference experiments suggest that SMAD4^R361^H/C mutations confer BVZ and 5-fluorouracil (5-FU) resistance through STAT3 signaling. Notably, supplementing BVZ and 5-FU with the STAT3 inhibitor GB201 restores therapeutic efficacy in SMAD4^R361^H/C cancer cells. Our study uncovers the evolutionary dynamics of CRLM and its microenvironment during treatment and offers strategies to overcome drug resistance.

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化疗下结直肠肝转移的遗传和微环境演变。

耐药性限制了化疗治疗结直肠癌肝转移（CRLM）的疗效。然而，CRLM在药物治疗过程中的演变尚不清楚。来自49例接受贝伐单抗（BVZ）化疗的CRLM患者的115个样本的多组学和治疗反应数据显示，92%的病例的基因组改变差异不大，而在转录组水平上观察到显着差异。通过将内在和获得性耐药解耦，我们发现肝细胞和髓细胞浸润分别占获得性耐药的38.5%和23.1%。重要的是，SMAD4突变和chr20q拷贝数增加与内在化学耐药有关。基因干扰实验表明SMAD4R361H/C突变通过STAT3信号传导赋予BVZ和5-氟尿嘧啶（5-FU）抗性。值得注意的是，用STAT3抑制剂GB201补充BVZ和5-FU可以恢复SMAD4R361H/C癌细胞的治疗效果。我们的研究揭示了CRLM及其微环境在治疗过程中的进化动力学，并提供了克服耐药的策略。

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

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.