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-side 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.

中文翻译：

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AFDN 缺陷促进转移性结直肠癌的嗜肝性


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嗜肝和转移的生物学机制有助于确定改进的预防和治疗策略。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 功能丧失筛选，并确定了 AFDN 的缺陷，AFDN 是一种参与建立和维持细胞间接触的蛋白质，是肝转移的驱动因素。AFDN 表达升高与结直肠癌患者生存期延长相关。AFDN 缺陷的结直肠癌细胞优先转移到肝脏，但不转移到肺部。原发部位结直肠癌细胞中 AFDN 的缺失通过破坏紧密的细胞间连接来促进癌细胞迁移和侵袭。此外，CXCR4 在 AFDN 缺陷的结直肠癌细胞中通过 JAK-STAT 信号通路增加表达，这降低了 AFDN 缺陷结直肠癌细胞的运动性并促进了它们在肝脏的定植。总的来说，这些数据阐明了 AFDN 缺陷促进转移性结直肠癌嗜肝性的机制。