DDR1 is identified as an immunotherapy target for microsatellite stable colon cancer by CRISPR screening
Abstract The role of collagen and its receptor, discoidin domain receptor 1 (DDR1) in immune response of colorectal cancer (CRC) remains unclear. We identified DDR1 as a promising target of immunotherapy resistance using a pooled in vivo CRISPR/sgRNA screening in microsatellite stable (MSS) CRC mous...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-11-01
|
| Series: | npj Precision Oncology |
| Online Access: | https://doi.org/10.1038/s41698-024-00743-2 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850195929421840384 |
|---|---|
| author | Miaoqing Wu Wenjuan Ma Guangzhao Lv Xin Wang Cong Li Xiang Chen Xiaofei Peng Chaoming Tang Zhizhong Pan Ranyi Liu Gong Chen Rongxin Zhang |
| author_facet | Miaoqing Wu Wenjuan Ma Guangzhao Lv Xin Wang Cong Li Xiang Chen Xiaofei Peng Chaoming Tang Zhizhong Pan Ranyi Liu Gong Chen Rongxin Zhang |
| author_sort | Miaoqing Wu |
| collection | DOAJ |
| description | Abstract The role of collagen and its receptor, discoidin domain receptor 1 (DDR1) in immune response of colorectal cancer (CRC) remains unclear. We identified DDR1 as a promising target of immunotherapy resistance using a pooled in vivo CRISPR/sgRNA screening in microsatellite stable (MSS) CRC mouse models. Our findings demonstrated that knockdown or inhibition of DDR1 could enhance infiltration of CD8+ T cells and sensitize MSS CRC to PD-1 blockade. Furthermore, DDR1 was found to facilitate kinase domain phosphorylation, upregulate EZH2, consequently elevating H3K27me3 levels at the CXCL10 promotor, which led to the suppression of CXCL10 transcription once bound to collagen in ECM. Lastly, DDR1 was found positively correlated with collagen I expression in MSS CRC specimens. These findings indicated that targeting DDR1 or its inhibitor 7rh might be potential strategy for overcoming immunotherapy resistance in MSS CRC. |
| format | Article |
| id | doaj-art-ce67629e4b56445d8635fb433ab5d4ea |
| institution | OA Journals |
| issn | 2397-768X |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Precision Oncology |
| spelling | doaj-art-ce67629e4b56445d8635fb433ab5d4ea2025-08-20T02:13:36ZengNature Portfolionpj Precision Oncology2397-768X2024-11-018111110.1038/s41698-024-00743-2DDR1 is identified as an immunotherapy target for microsatellite stable colon cancer by CRISPR screeningMiaoqing Wu0Wenjuan Ma1Guangzhao Lv2Xin Wang3Cong Li4Xiang Chen5Xiaofei Peng6Chaoming Tang7Zhizhong Pan8Ranyi Liu9Gong Chen10Rongxin Zhang11Department of Colorectal Surgery, Sun Yat-sen University Cancer CentreDepartment of Colorectal Surgery, Sun Yat-sen University Cancer CentreDepartment of Colorectal Surgery, Sun Yat-sen University Cancer CentreThe Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s HospitalDepartment of Colorectal Surgery, Sun Yat-sen University Cancer CentreThe Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s HospitalThe Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s HospitalThe Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s HospitalDepartment of Colorectal Surgery, Sun Yat-sen University Cancer CentreDepartment of Colorectal Surgery, Sun Yat-sen University Cancer CentreDepartment of Colorectal Surgery, Sun Yat-sen University Cancer CentreDepartment of Colorectal Surgery, Sun Yat-sen University Cancer CentreAbstract The role of collagen and its receptor, discoidin domain receptor 1 (DDR1) in immune response of colorectal cancer (CRC) remains unclear. We identified DDR1 as a promising target of immunotherapy resistance using a pooled in vivo CRISPR/sgRNA screening in microsatellite stable (MSS) CRC mouse models. Our findings demonstrated that knockdown or inhibition of DDR1 could enhance infiltration of CD8+ T cells and sensitize MSS CRC to PD-1 blockade. Furthermore, DDR1 was found to facilitate kinase domain phosphorylation, upregulate EZH2, consequently elevating H3K27me3 levels at the CXCL10 promotor, which led to the suppression of CXCL10 transcription once bound to collagen in ECM. Lastly, DDR1 was found positively correlated with collagen I expression in MSS CRC specimens. These findings indicated that targeting DDR1 or its inhibitor 7rh might be potential strategy for overcoming immunotherapy resistance in MSS CRC.https://doi.org/10.1038/s41698-024-00743-2 |
| spellingShingle | Miaoqing Wu Wenjuan Ma Guangzhao Lv Xin Wang Cong Li Xiang Chen Xiaofei Peng Chaoming Tang Zhizhong Pan Ranyi Liu Gong Chen Rongxin Zhang DDR1 is identified as an immunotherapy target for microsatellite stable colon cancer by CRISPR screening npj Precision Oncology |
| title | DDR1 is identified as an immunotherapy target for microsatellite stable colon cancer by CRISPR screening |
| title_full | DDR1 is identified as an immunotherapy target for microsatellite stable colon cancer by CRISPR screening |
| title_fullStr | DDR1 is identified as an immunotherapy target for microsatellite stable colon cancer by CRISPR screening |
| title_full_unstemmed | DDR1 is identified as an immunotherapy target for microsatellite stable colon cancer by CRISPR screening |
| title_short | DDR1 is identified as an immunotherapy target for microsatellite stable colon cancer by CRISPR screening |
| title_sort | ddr1 is identified as an immunotherapy target for microsatellite stable colon cancer by crispr screening |
| url | https://doi.org/10.1038/s41698-024-00743-2 |
| work_keys_str_mv | AT miaoqingwu ddr1isidentifiedasanimmunotherapytargetformicrosatellitestablecoloncancerbycrisprscreening AT wenjuanma ddr1isidentifiedasanimmunotherapytargetformicrosatellitestablecoloncancerbycrisprscreening AT guangzhaolv ddr1isidentifiedasanimmunotherapytargetformicrosatellitestablecoloncancerbycrisprscreening AT xinwang ddr1isidentifiedasanimmunotherapytargetformicrosatellitestablecoloncancerbycrisprscreening AT congli ddr1isidentifiedasanimmunotherapytargetformicrosatellitestablecoloncancerbycrisprscreening AT xiangchen ddr1isidentifiedasanimmunotherapytargetformicrosatellitestablecoloncancerbycrisprscreening AT xiaofeipeng ddr1isidentifiedasanimmunotherapytargetformicrosatellitestablecoloncancerbycrisprscreening AT chaomingtang ddr1isidentifiedasanimmunotherapytargetformicrosatellitestablecoloncancerbycrisprscreening AT zhizhongpan ddr1isidentifiedasanimmunotherapytargetformicrosatellitestablecoloncancerbycrisprscreening AT ranyiliu ddr1isidentifiedasanimmunotherapytargetformicrosatellitestablecoloncancerbycrisprscreening AT gongchen ddr1isidentifiedasanimmunotherapytargetformicrosatellitestablecoloncancerbycrisprscreening AT rongxinzhang ddr1isidentifiedasanimmunotherapytargetformicrosatellitestablecoloncancerbycrisprscreening |