Data from Th17 Cells Secrete TWEAK to Trigger Epithelial–Mesenchymal Transition and Promote Colorectal Cancer Liver Metastasis

• DOI: 10.1158/0008-5472.c.7181314.v2
• Publication Date: 2024-04-15T18:21:44Z
• Authors: Xin Liu; Xin Wang; Qingxia Yang; Li Luo; Ziqin Liu; Xiaoxue Ren; Kai Lei; Shangru Li; Zonglin Xie; Gaomin Zheng; Yifan Zhang; Yijie Hao; Qianying Zhou; Yingdong Hou; Fei Fang; Wu Song; Ji Cui; Jinping Ma; Wenxuan Xie; Shunli Shen; Ce Tang; Sui Peng; Jun Yu; Ming Kuang; Xinming Song; Fang Wang; Lixia Xu

<div>Abstract<p>Liver metastasis is the leading cause of mortality in patients with colorectal cancer. Given significance both epithelial–mesenchymal transition (EMT) tumor cells and immune microenvironment cancer liver (CRLM), interplay between them could hold key for developing improved treatment options. We employed multiomics analysis 130 samples from 18 synchronous CRLM integrated external datasets to comprehensively evaluate interaction EMT metastasis. Single-cell RNA sequencing revealed distinct distributions nonmalignant primary tumors metastatic (mCRC) non-metastatic cancer, showing that Th17 were predominantly enriched lesion mCRC. TWEAK, a cytokine secreted by cells, promoted binding receptor Fn14 on TWEAK–Fn14 enhanced migration invasion. In mouse models, targeting using CRISPR-induced knockout or lipid nanoparticle–encapsulated siRNA alleviated prolonged survival. Mice lacking <i>Il17a</i> <i>Tnfsf12</i> (encoding TWEAK) exhibited fewer metastases compared wild-type mice, while cotransfer Higher TWEAK expression was associated worse prognosis addition, CD163L1<sup>+</sup> macrophages interacted recruiting via CCL4-CCR5 axis. Collectively, this study unveils role process identifies as driver CRLM.</p>Significance:<p>TWEAK promotes suggesting blocking may be promising therapeutic approach inhibit metastasis.</p></div>