Cancer-associated fibroblast-derived SEMA3C facilitates colorectal cancer liver metastasis via NRP2-mediated MAPK activation.

IF 9.4 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-05-22 DOI:10.1073/pnas.2423077122

Yuyuan Zhang,Anning Zuo,Yuhao Ba,Shutong Liu,Jingqi Chen,Shuaixi Yang,Siyuan Weng,Yukang Chen,Hui Xu,Peng Luo,Quan Cheng,Bufu Tang,Benyu Liu,Chuhan Zhang,Jingkuan Yang,Xinwei Han,Zaoqu Liu

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Abstract

Liver metastasis remains the predominant cause of mortality in patients with colorectal cancer (CRC). Nevertheless, the mechanisms underlying the initiation of colorectal cancer liver metastasis remain poorly elucidated. During the metastatic process of CRC cells from the primary site to the liver, we performed time-resolved analyses and identified a subset of tumor cells spatially located in the primary tumor and temporally distributed in the early stages of liver metastasis. These cells were termed liver metastasis-initiating cells (LMICs). LMICs exhibit high stemness, low proliferation, active interaction with surrounding stromal components, and a close association with liver metastasis. Notably, we found significant interactions between cancer-associated fibroblasts (CAFs) and LMICs via the SEMA3C-NRP2 receptor-ligand pair. Further in vivo and in vitro experiments confirmed that CAF-secreted SEMA3C could bind to the NRP2 receptor, which activates the MAPK pathway and promotes colorectal cancer liver metastasis. Our findings suggest potential therapeutic strategies for the early prevention of colorectal cancer liver metastasis.

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癌症相关成纤维细胞衍生的SEMA3C通过nrp2介导的MAPK激活促进结直肠癌肝转移。

肝转移仍然是结直肠癌（CRC）患者死亡的主要原因。然而，结直肠癌肝转移发生的机制仍不清楚。在CRC细胞从原发部位转移到肝脏的过程中，我们进行了时间分辨分析，并确定了一部分肿瘤细胞在空间上位于原发肿瘤，在时间上分布于肝转移的早期阶段。这些细胞被称为肝转移起始细胞（LMICs）。LMICs表现出高干性、低增殖、与周围基质成分积极相互作用，并与肝转移密切相关。值得注意的是，我们发现癌症相关成纤维细胞（CAFs）和LMICs之间通过SEMA3C-NRP2受体-配体对存在显著的相互作用。进一步的体内和体外实验证实，caf分泌的SEMA3C可与NRP2受体结合，激活MAPK通路，促进结直肠癌肝转移。我们的研究结果为早期预防结直肠癌肝转移提供了潜在的治疗策略。

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

Proceedings of the National Academy of Sciences of the United States of America 综合性期刊-综合性期刊

CiteScore

19.00

自引率

0.90%

发文量

3575

审稿时长

2.5 months

期刊介绍： The Proceedings of the National Academy of Sciences (PNAS), a peer-reviewed journal of the National Academy of Sciences (NAS), serves as an authoritative source for high-impact, original research across the biological, physical, and social sciences. With a global scope, the journal welcomes submissions from researchers worldwide, making it an inclusive platform for advancing scientific knowledge.