5‐hydroxymethylcytosine features of portal venous blood predict metachronous liver metastases of colorectal cancer and reveal phosphodiesterase 4 as a therapeutic target
Abstract Metachronous liver metastases (MLM) are characterised by high incidence and high mortality in clinical colorectal cancer treatment. Currently traditional clinical methods cannot effectively predict and prevent the occurrence of metachronous liver metastasis in colorectal cancer. Based on 5h...
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2025-02-01
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| Online Access: | https://doi.org/10.1002/ctm2.70189 |
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| author | Nuo Xu Zhaoya Gao Deyan Wu Hangyu Chen Zijian Zhang Lei Zhang Yuchen Wang Xuyang Lu Xu Yao Xuelan Liu Yi‐You Huang Meiying Qiu Sen Wang Jinqiang Liang Can Mao Feng Zhang Huimin Xu Yujiao Wang Xian Li Zhexin Chen Dandan Huang Jingyi Shi Wensheng Huang Fuming Lei Zeruo Yang Long Chen Chuan He Haichuan Zhu Hai‐Bin Luo Jin Gu Jian Lin |
| author_facet | Nuo Xu Zhaoya Gao Deyan Wu Hangyu Chen Zijian Zhang Lei Zhang Yuchen Wang Xuyang Lu Xu Yao Xuelan Liu Yi‐You Huang Meiying Qiu Sen Wang Jinqiang Liang Can Mao Feng Zhang Huimin Xu Yujiao Wang Xian Li Zhexin Chen Dandan Huang Jingyi Shi Wensheng Huang Fuming Lei Zeruo Yang Long Chen Chuan He Haichuan Zhu Hai‐Bin Luo Jin Gu Jian Lin |
| author_sort | Nuo Xu |
| collection | DOAJ |
| description | Abstract Metachronous liver metastases (MLM) are characterised by high incidence and high mortality in clinical colorectal cancer treatment. Currently traditional clinical methods cannot effectively predict and prevent the occurrence of metachronous liver metastasis in colorectal cancer. Based on 5hmC‐Seal analysis of blood and tissue samples, this study found that portal venous blood was more relevant to tumour gDNA than peripheral blood. We performed a novel epigenetic liquid biopsy strategy using the 10 5hmC epigenetic alterations, to accurately distinguish MLM patients from patients without metastases. Among these epigenetic alterations, phosphodiesterase 4 (PDE4D) was highly increased in MLM patients and correlated with poor survival. Moreover, our studies demonstrated that PDE4D was a key metastasis‐driven target for drug development. Interfering with the function of PDE4D significantly repressed liver metastases. Similarly, roflumilast, a PDE4 inhibitor for chronic obstructive pulmonary disease (COPD) therapy, also inhibits liver metastases. Further studies indicate that blocking the function of PDE4D can affect CRC invasion through the HIF‐1α‐CCN2 pathway. To develop a more efficient PDE4 inhibitor and reduce the occurrence of adverse events, we also designed several new compounds based on 2‐arylbenzofurans and discovered lead L11 with potent affinity for PDE4D and significant suppression of liver metastases. In this work, our study provides a promising strategy for predicting metachronous liver metastasis and discovers L11 as a potential repurposed drug for inhibiting liver metastasis, which have the potential to benefit patients with CRC in the future. Key points 5hmC epigenetic markers derived from portal venous blood could accurately predict metachronous metastasis of colorectal cancer. PDE4D was a key metastasis‐driven target that promoted metachronous metastasis via the HIF‐1α‐CCN2 pathway. The newly synthesised compound L11 could specifically inhibit PDE4D and abolish metachronous metastasis of colorectal cancer without obvious toxic side effects. |
| format | Article |
| id | doaj-art-fa3b84c42c7c49a0b740ea40aaa256d5 |
| institution | OA Journals |
| issn | 2001-1326 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
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| series | Clinical and Translational Medicine |
| spelling | doaj-art-fa3b84c42c7c49a0b740ea40aaa256d52025-08-20T02:15:50ZengWileyClinical and Translational Medicine2001-13262025-02-01152n/an/a10.1002/ctm2.701895‐hydroxymethylcytosine features of portal venous blood predict metachronous liver metastases of colorectal cancer and reveal phosphodiesterase 4 as a therapeutic targetNuo Xu0Zhaoya Gao1Deyan Wu2Hangyu Chen3Zijian Zhang4Lei Zhang5Yuchen Wang6Xuyang Lu7Xu Yao8Xuelan Liu9Yi‐You Huang10Meiying Qiu11Sen Wang12Jinqiang Liang13Can Mao14Feng Zhang15Huimin Xu16Yujiao Wang17Xian Li18Zhexin Chen19Dandan Huang20Jingyi Shi21Wensheng Huang22Fuming Lei23Zeruo Yang24Long Chen25Chuan He26Haichuan Zhu27Hai‐Bin Luo28Jin Gu29Jian Lin30Department of Pharmacy Peking University Third Hospital Beijing ChinaDepartment of Gastrointestinal Surgery Peking University Shougang Hospital Beijing ChinaKey Laboratory of Tropical Biological Resources of Ministry of Education School of Pharmaceutical Sciences Hainan University Haikou Hainan ChinaDepartment of Pharmacy Peking University Third Hospital Beijing ChinaKey Laboratory of Tropical Biological Resources of Ministry of Education School of Pharmaceutical Sciences Hainan University Haikou Hainan ChinaNatural Medicine Institute of Zhejiang YangShengTang Co. Ltd. Hangzhou ChinaNatural Medicine Institute of Zhejiang YangShengTang Co. Ltd. Hangzhou ChinaNatural Medicine Institute of Zhejiang YangShengTang Co. Ltd. Hangzhou ChinaNatural Medicine Institute of Zhejiang YangShengTang Co. Ltd. Hangzhou ChinaNatural Medicine Institute of Zhejiang YangShengTang Co. Ltd. Hangzhou ChinaKey Laboratory of Tropical Biological Resources of Ministry of Education School of Pharmaceutical Sciences Hainan University Haikou Hainan ChinaSchool of Pharmaceutical Sciences Sun Yat‐sen University Guangzhou ChinaKey Laboratory of Tropical Biological Resources of Ministry of Education School of Pharmaceutical Sciences Hainan University Haikou Hainan ChinaKey Laboratory of Tropical Biological Resources of Ministry of Education School of Pharmaceutical Sciences Hainan University Haikou Hainan ChinaKey Laboratory of Tropical Biological Resources of Ministry of Education School of Pharmaceutical Sciences Hainan University Haikou Hainan ChinaKey Laboratory of Tropical Biological Resources of Ministry of Education School of Pharmaceutical Sciences Hainan University Haikou Hainan ChinaKey Laboratory of Tropical Biological Resources of Ministry of Education School of Pharmaceutical Sciences Hainan University Haikou Hainan ChinaKey Laboratory of Tropical Biological Resources of Ministry of Education School of Pharmaceutical Sciences Hainan University Haikou Hainan ChinaKey Laboratory of Tropical Biological Resources of Ministry of Education School of Pharmaceutical Sciences Hainan University Haikou Hainan ChinaKey Laboratory of Tropical Biological Resources of Ministry of Education School of Pharmaceutical Sciences Hainan University Haikou Hainan ChinaCenter for Precision Diagnosis and Treatment of Colorectal Cancer and Inflammatory Diseases Peking University Health Science Center Beijing ChinaKey laboratory of Carcinogenesis & Translational Research (Ministry of Education), Department of Gastrointestinal Surgery III Peking University Cancer Hospital & Institute Beijing ChinaDepartment of Gastrointestinal Surgery Peking University Shougang Hospital Beijing ChinaDepartment of Gastrointestinal Surgery Peking University Shougang Hospital Beijing ChinaDepartment of Pharmacy Peking University Third Hospital Beijing ChinaDepartment of Pharmacy Peking University Third Hospital Beijing ChinaDepartment of Chemistry Department of Biochemistry and Molecular Biology Howard Hughes Medical Institute The University of Chicago Chicago Illinois USAInstitute of Biology and Medicine College of Life and Health Sciences Wuhan University of Science and Technology Wuhan ChinaKey Laboratory of Tropical Biological Resources of Ministry of Education School of Pharmaceutical Sciences Hainan University Haikou Hainan ChinaDepartment of Gastrointestinal Surgery Peking University Shougang Hospital Beijing ChinaDepartment of Pharmacy Peking University Third Hospital Beijing ChinaAbstract Metachronous liver metastases (MLM) are characterised by high incidence and high mortality in clinical colorectal cancer treatment. Currently traditional clinical methods cannot effectively predict and prevent the occurrence of metachronous liver metastasis in colorectal cancer. Based on 5hmC‐Seal analysis of blood and tissue samples, this study found that portal venous blood was more relevant to tumour gDNA than peripheral blood. We performed a novel epigenetic liquid biopsy strategy using the 10 5hmC epigenetic alterations, to accurately distinguish MLM patients from patients without metastases. Among these epigenetic alterations, phosphodiesterase 4 (PDE4D) was highly increased in MLM patients and correlated with poor survival. Moreover, our studies demonstrated that PDE4D was a key metastasis‐driven target for drug development. Interfering with the function of PDE4D significantly repressed liver metastases. Similarly, roflumilast, a PDE4 inhibitor for chronic obstructive pulmonary disease (COPD) therapy, also inhibits liver metastases. Further studies indicate that blocking the function of PDE4D can affect CRC invasion through the HIF‐1α‐CCN2 pathway. To develop a more efficient PDE4 inhibitor and reduce the occurrence of adverse events, we also designed several new compounds based on 2‐arylbenzofurans and discovered lead L11 with potent affinity for PDE4D and significant suppression of liver metastases. In this work, our study provides a promising strategy for predicting metachronous liver metastasis and discovers L11 as a potential repurposed drug for inhibiting liver metastasis, which have the potential to benefit patients with CRC in the future. Key points 5hmC epigenetic markers derived from portal venous blood could accurately predict metachronous metastasis of colorectal cancer. PDE4D was a key metastasis‐driven target that promoted metachronous metastasis via the HIF‐1α‐CCN2 pathway. The newly synthesised compound L11 could specifically inhibit PDE4D and abolish metachronous metastasis of colorectal cancer without obvious toxic side effects.https://doi.org/10.1002/ctm2.701895hmC‐SealColorectal cancerMetachronous liver metastasesPDE4D |
| spellingShingle | Nuo Xu Zhaoya Gao Deyan Wu Hangyu Chen Zijian Zhang Lei Zhang Yuchen Wang Xuyang Lu Xu Yao Xuelan Liu Yi‐You Huang Meiying Qiu Sen Wang Jinqiang Liang Can Mao Feng Zhang Huimin Xu Yujiao Wang Xian Li Zhexin Chen Dandan Huang Jingyi Shi Wensheng Huang Fuming Lei Zeruo Yang Long Chen Chuan He Haichuan Zhu Hai‐Bin Luo Jin Gu Jian Lin 5‐hydroxymethylcytosine features of portal venous blood predict metachronous liver metastases of colorectal cancer and reveal phosphodiesterase 4 as a therapeutic target Clinical and Translational Medicine 5hmC‐Seal Colorectal cancer Metachronous liver metastases PDE4D |
| title | 5‐hydroxymethylcytosine features of portal venous blood predict metachronous liver metastases of colorectal cancer and reveal phosphodiesterase 4 as a therapeutic target |
| title_full | 5‐hydroxymethylcytosine features of portal venous blood predict metachronous liver metastases of colorectal cancer and reveal phosphodiesterase 4 as a therapeutic target |
| title_fullStr | 5‐hydroxymethylcytosine features of portal venous blood predict metachronous liver metastases of colorectal cancer and reveal phosphodiesterase 4 as a therapeutic target |
| title_full_unstemmed | 5‐hydroxymethylcytosine features of portal venous blood predict metachronous liver metastases of colorectal cancer and reveal phosphodiesterase 4 as a therapeutic target |
| title_short | 5‐hydroxymethylcytosine features of portal venous blood predict metachronous liver metastases of colorectal cancer and reveal phosphodiesterase 4 as a therapeutic target |
| title_sort | 5 hydroxymethylcytosine features of portal venous blood predict metachronous liver metastases of colorectal cancer and reveal phosphodiesterase 4 as a therapeutic target |
| topic | 5hmC‐Seal Colorectal cancer Metachronous liver metastases PDE4D |
| url | https://doi.org/10.1002/ctm2.70189 |
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