AFDN Deficiency Promotes Liver Tropism of Metastatic Colorectal Cancer.

IF 12.5 1区 医学 Q1 ONCOLOGY Cancer research Pub Date : 2024-10-01 DOI:10.1158/0008-5472.CAN-23-3140
Shaoxia Liao, Jingwen Deng, Mengli Deng, Chaoyi Chen, Fengyan Han, Kehong Ye, Chenxia Wu, Lvyuan Pan, Maode Lai, Zhe Tang, Honghe Zhang
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Abstract

Liver metastasis is a major cause of morbidity and mortality in patients with colorectal cancer. A better understanding of the biological mechanisms underlying liver tropism and metastasis in colorectal cancer could help to identify improved prevention and treatment strategies. In this study, we performed genome-wide CRISPR loss-of-function screening in a mouse colorectal cancer model and identified deficiency of AFDN, a protein involved in establishing and maintaining cell-cell contacts, as a driver of liver metastasis. Elevated AFDN expression was correlated with prolonged survival in patients with colorectal cancer. AFDN-deficient colorectal cancer cells preferentially metastasized to the liver but not in the lungs. AFDN loss in colorectal cancer cells at the primary site promoted cancer cell migration and invasion by disrupting tight intercellular junctions. Additionally, CXCR4 expression was increased in AFDN-deficient colorectal cancer cells via the JAK-STAT signaling pathway, which reduced the motility of AFDN-deficient colorectal cancer cells and facilitated their colonization of the liver. Collectively, these data shed light on the mechanism by which AFDN deficiency promotes liver tropism in metastatic colorectal cancer. Significance: A CRISPR screen reveals AFDN loss as a mediator of liver tropism in colorectal cancer metastasis by decreasing tight junctions in the primary tumor and increasing interactions between cancer cells and hepatocytes.

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AFDN 缺乏会促进转移性结直肠癌的肝趋向性。
肝转移是结直肠癌患者发病和死亡的主要原因。更好地了解结直肠癌肝脏滋养和转移的生物学机制有助于确定更好的预防和治疗策略。在这项研究中,我们在小鼠结直肠癌模型中进行了基因组侧CRISPR功能缺失筛选,发现AFDN(一种参与建立和维持细胞-细胞接触的蛋白质)的缺乏是肝转移的驱动因素。AFDN 表达的升高与结直肠癌患者生存期的延长相关。AFDN缺失的结直肠癌细胞会优先转移到肝脏,但不会转移到肺部。原发部位结直肠癌细胞中 AFDN 的缺失通过破坏细胞间的紧密连接促进了癌细胞的迁移和侵袭。此外,缺失 AFDN 的结直肠癌细胞通过 JAK-STAT 信号通路增加了 CXCR4 的表达,这降低了缺失 AFDN 的结直肠癌细胞的运动能力,并促进了它们在肝脏的定植。总之,这些数据揭示了AFDN缺陷促进转移性结直肠癌肝趋向的机制。
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来源期刊
Cancer research
Cancer research 医学-肿瘤学
CiteScore
16.10
自引率
0.90%
发文量
7677
审稿时长
2.5 months
期刊介绍: Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.
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