Targeting SLITRK4 Restrains Proliferation and Liver Metastasis in Colorectal Cancer via Regulating PI3K/AKT/NFκB Pathway and Tumor‐Associated Macrophage
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...
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| Format: | Article |
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Wiley
2025-01-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202400367 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Xiaojiao Sun |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-6411fc0617264c88be24a6bf6ede4900 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-6411fc0617264c88be24a6bf6ede49002025-01-09T11:44:45ZengWileyAdvanced Science2198-38442025-01-01121n/an/a10.1002/advs.202400367Targeting SLITRK4 Restrains Proliferation and Liver Metastasis in Colorectal Cancer via Regulating PI3K/AKT/NFκB Pathway and Tumor‐Associated MacrophageXiaojiao Sun0Junling Zhang1Bingqi Dong2Qingqing Xiong3Xin Wang4Yanlun Gu5Zhiqi Wang6Huiyu Liu7Jixin Zhang8Xu He9Hongjin Liu10Yi Zhong11Chuxiao Yi12Xiaowei Chi13Zhenming Liu14Xiaocong Pang15Yimin Cui16State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences Peking University Beijing 100191 ChinaDepartment of General Surgery Peking University First Hospital Xishiku Street, Beijing Xicheng 100034 ChinaDepartment of General Surgery Peking University First Hospital Xishiku Street, Beijing Xicheng 100034 ChinaDepartment of Hepatobiliary Cancer Liver Cancer Center Tianjin Medical University Cancer Institute Tianjin 300060 ChinaDepartment of General Surgery Peking University First Hospital Xishiku Street, Beijing Xicheng 100034 ChinaState Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences Peking University Beijing 100191 ChinaState Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences Peking University Beijing 100191 ChinaState Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences Peking University Beijing 100191 ChinaDepartment of Pathology Peking University First Hospital Xishiku Street, Beijing Xicheng 100034 ChinaDepartment of Pharmacy Peking University First Hospital Xishiku Street, Beijing Xicheng 100034 ChinaDepartment of General Surgery Peking University First Hospital Xishiku Street, Beijing Xicheng 100034 ChinaState Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences Peking University Beijing 100191 ChinaState Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences Peking University Beijing 100191 ChinaState Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences Peking University Beijing 100191 ChinaState Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences Peking University Beijing 100191 ChinaState Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences Peking University Beijing 100191 ChinaState Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences Peking University Beijing 100191 ChinaAbstract 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.https://doi.org/10.1002/advs.202400367colorectal cancerliver metastasismacrophagenanoparticlesSLITRK4 |
| spellingShingle | 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 Targeting SLITRK4 Restrains Proliferation and Liver Metastasis in Colorectal Cancer via Regulating PI3K/AKT/NFκB Pathway and Tumor‐Associated Macrophage Advanced Science colorectal cancer liver metastasis macrophage nanoparticles SLITRK4 |
| title | Targeting SLITRK4 Restrains Proliferation and Liver Metastasis in Colorectal Cancer via Regulating PI3K/AKT/NFκB Pathway and Tumor‐Associated Macrophage |
| title_full | Targeting SLITRK4 Restrains Proliferation and Liver Metastasis in Colorectal Cancer via Regulating PI3K/AKT/NFκB Pathway and Tumor‐Associated Macrophage |
| title_fullStr | Targeting SLITRK4 Restrains Proliferation and Liver Metastasis in Colorectal Cancer via Regulating PI3K/AKT/NFκB Pathway and Tumor‐Associated Macrophage |
| title_full_unstemmed | Targeting SLITRK4 Restrains Proliferation and Liver Metastasis in Colorectal Cancer via Regulating PI3K/AKT/NFκB Pathway and Tumor‐Associated Macrophage |
| title_short | Targeting SLITRK4 Restrains Proliferation and Liver Metastasis in Colorectal Cancer via Regulating PI3K/AKT/NFκB Pathway and Tumor‐Associated Macrophage |
| title_sort | targeting slitrk4 restrains proliferation and liver metastasis in colorectal cancer via regulating pi3k akt nfκb pathway and tumor associated macrophage |
| topic | colorectal cancer liver metastasis macrophage nanoparticles SLITRK4 |
| url | https://doi.org/10.1002/advs.202400367 |
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