PI3K/AKT/mTOR通路
癌症研究
转移
结直肠癌
医学
蛋白激酶B
癌症
巨噬细胞
信号转导
内科学
生物
细胞生物学
生物化学
体外
作者
Xiaojiao Sun,Junling Zhang,Bingqi Dong,Qingqing Xiong,Xin Wang,Yanlun Gu,Zhiqi Wang,Huiyu Liu,Jixin Zhang,Xu He,Hongjin Liu,Yi Zhong,Chuxiao Yi,Xiaowei Chi,Zhenming Liu,Xiaocong Pang,Yimin Cui
标识
DOI:10.1002/advs.202400367
摘要
Abstract Liver metastasis is the major cause of death in colorectal cancer (CRC) due to the lack of effective treatment. To explore novel drivers of CRC liver metastasis, the transcriptomes of primary paracancerous, colorectal tumors and metastases from human patients are profiled. It is found that SLIT‐ and NTRK‐like family member 4 (SLITRK4) is the top upregulated gene in liver metastases and is associated with worse overall survival of CRC patients. Multiple in vitro and in vivo models suggested SLITRK4 promoted CRC tumorigenesis, invasion, migration, and angiogenesis, and inhibition of it restrained CRC tumor growth and liver metastasis with a more profound effect on the tumor microenvironment (TME). Mechanistically, SLITRK4 overexpression significantly activated the PI3K/AKT/NFκB pathway, regulated extracellular matrix organization, and multiple cytokines expression. Furthermore, the results from coculture models and single‐cell RNA sequencing analyses suggested SLITRK4 promoted tumor‐associated macrophages (TAMs) infiltration and polarization. In addition, macrophage depletion significantly inhibited SLITRK4‐induced liver metastasis in CRC. Finally, pharmacological inhibition of SLITRK4 by using lipid‐polymer hybrid nanoparticles (NPs) for systemic siRNA delivery can effectively inhibit CRC liver metastasis. Taken together, these results pinpoint that SLITRK4 regulates CRC tumorigenesis and liver metastasis, and siRNA delivering NPs agents validate the therapeutic potential of targeting SLITRK4 in CRC.
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