Integrated chromatin and transcriptomic profiling of patient-derived colon cancer organoids identifies personalized drug targets to overcome oxaliplatin resistance
Colorectal cancer is a leading cause of cancer deaths. Most colorectal cancer patients eventually develop chemoresistance to the current standard-of-care therapies. Here, we used patient-derived colorectal cancer organoids to demonstrate that resistant tumor cells undergo significant chromatin chang...
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| Veröffentlicht in: | Genes & diseases 2021-03, Vol.8 (2), p.203-214 |
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| creator | Tung, Kuei-Ling Chen, Kai-Yuan Negrete, Marcos Chen, Tianyi Safi, Alexias Aljamal, Abed Alhalim Song, Lingyun Crawford, Gregory E. Ding, Shengli Hsu, David S. Shen, Xiling |
| description | Colorectal cancer is a leading cause of cancer deaths. Most colorectal cancer patients eventually develop chemoresistance to the current standard-of-care therapies. Here, we used patient-derived colorectal cancer organoids to demonstrate that resistant tumor cells undergo significant chromatin changes in response to oxaliplatin treatment. Integrated transcriptomic and chromatin accessibility analyses using ATAC-Seq and RNA-Seq identified a group of genes associated with significantly increased chromatin accessibility and upregulated gene expression. CRISPR/Cas9 silencing of fibroblast growth factor receptor 1 (FGFR1) and oxytocin receptor (OXTR) helped overcome oxaliplatin resistance. Similarly, treatment with oxaliplatin in combination with an FGFR1 inhibitor (PD166866) or an antagonist of OXTR (L-368,899) suppressed chemoresistant organoids. However, oxaliplatin treatment did not activate either FGFR1 or OXTR expression in another resistant organoid, suggesting that chromatin accessibility changes are patient-specific. The use of patient-derived cancer organoids in combination with transcriptomic and chromatin profiling may lead to precision treatments to overcome chemoresistance in colorectal cancer. |
| doi_str_mv | 10.1016/j.gendis.2019.10.012 |
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Most colorectal cancer patients eventually develop chemoresistance to the current standard-of-care therapies. Here, we used patient-derived colorectal cancer organoids to demonstrate that resistant tumor cells undergo significant chromatin changes in response to oxaliplatin treatment. Integrated transcriptomic and chromatin accessibility analyses using ATAC-Seq and RNA-Seq identified a group of genes associated with significantly increased chromatin accessibility and upregulated gene expression. CRISPR/Cas9 silencing of fibroblast growth factor receptor 1 (FGFR1) and oxytocin receptor (OXTR) helped overcome oxaliplatin resistance. Similarly, treatment with oxaliplatin in combination with an FGFR1 inhibitor (PD166866) or an antagonist of OXTR (L-368,899) suppressed chemoresistant organoids. However, oxaliplatin treatment did not activate either FGFR1 or OXTR expression in another resistant organoid, suggesting that chromatin accessibility changes are patient-specific. The use of patient-derived cancer organoids in combination with transcriptomic and chromatin profiling may lead to precision treatments to overcome chemoresistance in colorectal cancer.</description><identifier>ISSN: 2352-3042</identifier><identifier>ISSN: 2352-4820</identifier><identifier>EISSN: 2352-3042</identifier><identifier>DOI: 10.1016/j.gendis.2019.10.012</identifier><identifier>PMID: 33997167</identifier><language>eng</language><publisher>BEIJING: Elsevier B.V</publisher><subject>Biochemistry & Molecular Biology ; Chromatin accessibility ; Drug screening ; Full Length ; Genetics & Heredity ; Life Sciences & Biomedicine ; Patient-derived organoids ; Personalized medicine ; Science & Technology ; Target discovery</subject><ispartof>Genes & diseases, 2021-03, Vol.8 (2), p.203-214</ispartof><rights>2019 Chongqing Medical University</rights><rights>2019 Chongqing Medical University. Production and hosting by Elsevier B.V.</rights><rights>2019 Chongqing Medical University. 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The use of patient-derived cancer organoids in combination with transcriptomic and chromatin profiling may lead to precision treatments to overcome chemoresistance in colorectal cancer.</description><subject>Biochemistry & Molecular Biology</subject><subject>Chromatin accessibility</subject><subject>Drug screening</subject><subject>Full Length</subject><subject>Genetics & Heredity</subject><subject>Life Sciences & Biomedicine</subject><subject>Patient-derived organoids</subject><subject>Personalized medicine</subject><subject>Science & Technology</subject><subject>Target discovery</subject><issn>2352-3042</issn><issn>2352-4820</issn><issn>2352-3042</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>HGBXW</sourceid><sourceid>DOA</sourceid><recordid>eNqNkttu1DAQhiMEotXSN0DIl0hoF8eHJL5BQisOlSpxA9fWxJ6kXmXtYHuXw-vwojjdUtobxI1tjb_5PZ75q-p5TTc1rZvXu82I3rq0YbRWJbShNXtUnTMu2ZpTwR7fO59VFyntKKU151QK9bQ641yptm7a8-rXpc84RshoibmOYQ_ZeQLekhzBJxPdnMPeGTLHMLjJ-ZGEgcyFQp_XFqM7LplhCp4Y8AYjCXEEH5xNxNkCucFhIjPGFDxM7mfBbTyMJEMcMSeSAwlHjCbskYTvhZinmxoiJpfyIvmsejLAlPDidl9VX96_-7z9uL769OFy-_ZqbaSSeT3wTshOtgqanlM-gLS9ZLUB1aOSrBeDZTAgQ2yByWZZO6kYE0p2bSeAr6rLk64NsNNzdHuIP3QAp28C5V8aYnZmQm0MB1ubFqzsBGtRCd73DRqEoTVG0aL15qQ1H_o9WlMaEWF6IPrwxrtrPYaj7qhSTdcUgZe3AjF8PWDKeu-SwWkCj-GQNJOsE5yLMtVVJU6oiSGliMPdMzXVi130Tp_sohe7LNFil5L24n6Jd0l_zFGAVyfgG_ZhSKaM3OAdVgzVCMEbQRdrLVV0_09vXS5DDn4bDj7_bRaW6R4dRn2bbl1Ek0v73b-_8huDqfp_</recordid><startdate>20210301</startdate><enddate>20210301</enddate><creator>Tung, Kuei-Ling</creator><creator>Chen, Kai-Yuan</creator><creator>Negrete, Marcos</creator><creator>Chen, Tianyi</creator><creator>Safi, Alexias</creator><creator>Aljamal, Abed Alhalim</creator><creator>Song, Lingyun</creator><creator>Crawford, Gregory E.</creator><creator>Ding, Shengli</creator><creator>Hsu, David S.</creator><creator>Shen, Xiling</creator><general>Elsevier B.V</general><general>Keai Publishing Ltd</general><general>Chongqing Medical University</general><general>KeAi Communications Co., Ltd</general><scope>6I.</scope><scope>AAFTH</scope><scope>BLEPL</scope><scope>DTL</scope><scope>HGBXW</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-9247-8428</orcidid><orcidid>https://orcid.org/0009-0006-5587-1630</orcidid></search><sort><creationdate>20210301</creationdate><title>Integrated chromatin and transcriptomic profiling of patient-derived colon cancer organoids identifies personalized drug targets to overcome oxaliplatin resistance</title><author>Tung, Kuei-Ling ; 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| subjects | Biochemistry & Molecular Biology Chromatin accessibility Drug screening Full Length Genetics & Heredity Life Sciences & Biomedicine Patient-derived organoids Personalized medicine Science & Technology Target discovery |
| title | Integrated chromatin and transcriptomic profiling of patient-derived colon cancer organoids identifies personalized drug targets to overcome oxaliplatin resistance |
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