Regulatory enhancer profiling of mesenchymal-type gastric cancer reveals subtype-specific epigenomic landscapes and targetable vulnerabilities
ObjectiveGastric cancer (GC) comprises multiple molecular subtypes. Recent studies have highlighted mesenchymal-subtype GC (Mes-GC) as a clinically aggressive subtype with few treatment options. Combining multiple studies, we derived and applied a consensus Mes-GC classifier to define the Mes-GC enh...
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| Veröffentlicht in: | Gut 2023-02, Vol.72 (2), p.226-241 |
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| creator | Ho, Shamaine Wei Ting Sheng, Taotao Xing, Manjie Ooi, Wen Fong Xu, Chang Sundar, Raghav Huang, Kie Kyon Li, Zhimei Kumar, Vikrant Ramnarayanan, Kalpana Zhu, Feng Srivastava, Supriya Isa, Zul Fazreen Bin Adam Anene-Nzelu, Chukwuemeka George Razavi-Mohseni, Milad Shigaki, Dustin Ma, Haoran Tan, Angie Lay Keng Ong, Xuewen Lee, Ming Hui Tay, Su Ting Guo, Yu Amanda Huang, Weitai Li, Shang Beer, Michael A. Foo, Roger Sik Yin Teh, Ming Skanderup, Anders Jacobsen Teh, Bin Tean Tan, Patrick |
| description | ObjectiveGastric cancer (GC) comprises multiple molecular subtypes. Recent studies have highlighted mesenchymal-subtype GC (Mes-GC) as a clinically aggressive subtype with few treatment options. Combining multiple studies, we derived and applied a consensus Mes-GC classifier to define the Mes-GC enhancer landscape revealing disease vulnerabilities.DesignTranscriptomic profiles of ~1000 primary GCs and cell lines were analysed to derive a consensus Mes-GC classifier. Clinical and genomic associations were performed across >1200 patients with GC. Genome-wide epigenomic profiles (H3K27ac, H3K4me1 and assay for transposase-accessible chromatin with sequencing (ATAC-seq)) of 49 primary GCs and GC cell lines were generated to identify Mes-GC-specific enhancer landscapes. Upstream regulators and downstream targets of Mes-GC enhancers were interrogated using chromatin immunoprecipitation followed by sequencing (ChIP-seq), RNA sequencing, CRISPR/Cas9 editing, functional assays and pharmacological inhibition.ResultsWe identified and validated a 993-gene cancer-cell intrinsic Mes-GC classifier applicable to retrospective cohorts or prospective single samples. Multicohort analysis of Mes-GCs confirmed associations with poor patient survival, therapy resistance and few targetable genomic alterations. Analysis of enhancer profiles revealed a distinctive Mes-GC epigenomic landscape, with TEAD1 as a master regulator of Mes-GC enhancers and Mes-GCs exhibiting preferential sensitivity to TEAD1 pharmacological inhibition. Analysis of Mes-GC super-enhancers also highlighted NUAK1 kinase as a downstream target, with synergistic effects observed between NUAK1 inhibition and cisplatin treatment.ConclusionOur results establish a consensus Mes-GC classifier applicable to multiple transcriptomic scenarios. Mes-GCs exhibit a distinct epigenomic landscape, and TEAD1 inhibition and combinatorial NUAK1 inhibition/cisplatin may represent potential targetable options. |
| doi_str_mv | 10.1136/gutjnl-2021-326483 |
| format | Article |
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Recent studies have highlighted mesenchymal-subtype GC (Mes-GC) as a clinically aggressive subtype with few treatment options. Combining multiple studies, we derived and applied a consensus Mes-GC classifier to define the Mes-GC enhancer landscape revealing disease vulnerabilities.DesignTranscriptomic profiles of ~1000 primary GCs and cell lines were analysed to derive a consensus Mes-GC classifier. Clinical and genomic associations were performed across >1200 patients with GC. Genome-wide epigenomic profiles (H3K27ac, H3K4me1 and assay for transposase-accessible chromatin with sequencing (ATAC-seq)) of 49 primary GCs and GC cell lines were generated to identify Mes-GC-specific enhancer landscapes. Upstream regulators and downstream targets of Mes-GC enhancers were interrogated using chromatin immunoprecipitation followed by sequencing (ChIP-seq), RNA sequencing, CRISPR/Cas9 editing, functional assays and pharmacological inhibition.ResultsWe identified and validated a 993-gene cancer-cell intrinsic Mes-GC classifier applicable to retrospective cohorts or prospective single samples. Multicohort analysis of Mes-GCs confirmed associations with poor patient survival, therapy resistance and few targetable genomic alterations. Analysis of enhancer profiles revealed a distinctive Mes-GC epigenomic landscape, with TEAD1 as a master regulator of Mes-GC enhancers and Mes-GCs exhibiting preferential sensitivity to TEAD1 pharmacological inhibition. Analysis of Mes-GC super-enhancers also highlighted NUAK1 kinase as a downstream target, with synergistic effects observed between NUAK1 inhibition and cisplatin treatment.ConclusionOur results establish a consensus Mes-GC classifier applicable to multiple transcriptomic scenarios. Mes-GCs exhibit a distinct epigenomic landscape, and TEAD1 inhibition and combinatorial NUAK1 inhibition/cisplatin may represent potential targetable options.</description><identifier>ISSN: 0017-5749</identifier><identifier>EISSN: 1468-3288</identifier><identifier>DOI: 10.1136/gutjnl-2021-326483</identifier><identifier>PMID: 35817555</identifier><language>eng</language><publisher>England: BMJ Publishing Group Ltd and British Society of Gastroenterology</publisher><subject>Chromatin ; Cisplatin ; Cisplatin - metabolism ; Cisplatin - therapeutic use ; CRISPR ; Datasets ; DNA methylation ; Enhancer Elements, Genetic ; Enhancers ; Epigenesis, Genetic ; Gastric cancer ; Gene expression ; Gene Expression Regulation, Neoplastic ; Genomes ; Genomic analysis ; Humans ; Immunoprecipitation ; Kinases ; Medical prognosis ; Medical research ; Mesenchyme ; Mutation ; Patients ; Prospective Studies ; Protein Kinases - genetics ; Repressor Proteins ; Retrospective Studies ; RNA editing ; Stomach ; Stomach Neoplasms - genetics ; Transcriptomics ; Transposase ; Tumors</subject><ispartof>Gut, 2023-02, Vol.72 (2), p.226-241</ispartof><rights>Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.</rights><rights>2022 Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.</rights><rights>2023 Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b398t-95249aa8f2601f50367ec9ba685413b502deb9b9940e82028dc9732809dc3fd53</citedby><cites>FETCH-LOGICAL-b398t-95249aa8f2601f50367ec9ba685413b502deb9b9940e82028dc9732809dc3fd53</cites><orcidid>0000-0002-2595-0710 ; 0000-0001-9423-1368 ; 0000-0002-6052-3159 ; 0000-0002-0179-8048 ; 0000-0001-6030-9251 ; 0000-0003-4104-8951</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35817555$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ho, Shamaine Wei Ting</creatorcontrib><creatorcontrib>Sheng, Taotao</creatorcontrib><creatorcontrib>Xing, Manjie</creatorcontrib><creatorcontrib>Ooi, Wen Fong</creatorcontrib><creatorcontrib>Xu, Chang</creatorcontrib><creatorcontrib>Sundar, Raghav</creatorcontrib><creatorcontrib>Huang, Kie Kyon</creatorcontrib><creatorcontrib>Li, Zhimei</creatorcontrib><creatorcontrib>Kumar, Vikrant</creatorcontrib><creatorcontrib>Ramnarayanan, Kalpana</creatorcontrib><creatorcontrib>Zhu, Feng</creatorcontrib><creatorcontrib>Srivastava, Supriya</creatorcontrib><creatorcontrib>Isa, Zul Fazreen Bin Adam</creatorcontrib><creatorcontrib>Anene-Nzelu, Chukwuemeka George</creatorcontrib><creatorcontrib>Razavi-Mohseni, Milad</creatorcontrib><creatorcontrib>Shigaki, Dustin</creatorcontrib><creatorcontrib>Ma, Haoran</creatorcontrib><creatorcontrib>Tan, Angie Lay Keng</creatorcontrib><creatorcontrib>Ong, Xuewen</creatorcontrib><creatorcontrib>Lee, Ming Hui</creatorcontrib><creatorcontrib>Tay, Su Ting</creatorcontrib><creatorcontrib>Guo, Yu Amanda</creatorcontrib><creatorcontrib>Huang, Weitai</creatorcontrib><creatorcontrib>Li, Shang</creatorcontrib><creatorcontrib>Beer, Michael A.</creatorcontrib><creatorcontrib>Foo, Roger Sik Yin</creatorcontrib><creatorcontrib>Teh, Ming</creatorcontrib><creatorcontrib>Skanderup, Anders Jacobsen</creatorcontrib><creatorcontrib>Teh, Bin Tean</creatorcontrib><creatorcontrib>Tan, Patrick</creatorcontrib><title>Regulatory enhancer profiling of mesenchymal-type gastric cancer reveals subtype-specific epigenomic landscapes and targetable vulnerabilities</title><title>Gut</title><addtitle>Gut</addtitle><addtitle>Gut</addtitle><description>ObjectiveGastric cancer (GC) comprises multiple molecular subtypes. Recent studies have highlighted mesenchymal-subtype GC (Mes-GC) as a clinically aggressive subtype with few treatment options. Combining multiple studies, we derived and applied a consensus Mes-GC classifier to define the Mes-GC enhancer landscape revealing disease vulnerabilities.DesignTranscriptomic profiles of ~1000 primary GCs and cell lines were analysed to derive a consensus Mes-GC classifier. Clinical and genomic associations were performed across >1200 patients with GC. Genome-wide epigenomic profiles (H3K27ac, H3K4me1 and assay for transposase-accessible chromatin with sequencing (ATAC-seq)) of 49 primary GCs and GC cell lines were generated to identify Mes-GC-specific enhancer landscapes. Upstream regulators and downstream targets of Mes-GC enhancers were interrogated using chromatin immunoprecipitation followed by sequencing (ChIP-seq), RNA sequencing, CRISPR/Cas9 editing, functional assays and pharmacological inhibition.ResultsWe identified and validated a 993-gene cancer-cell intrinsic Mes-GC classifier applicable to retrospective cohorts or prospective single samples. Multicohort analysis of Mes-GCs confirmed associations with poor patient survival, therapy resistance and few targetable genomic alterations. Analysis of enhancer profiles revealed a distinctive Mes-GC epigenomic landscape, with TEAD1 as a master regulator of Mes-GC enhancers and Mes-GCs exhibiting preferential sensitivity to TEAD1 pharmacological inhibition. Analysis of Mes-GC super-enhancers also highlighted NUAK1 kinase as a downstream target, with synergistic effects observed between NUAK1 inhibition and cisplatin treatment.ConclusionOur results establish a consensus Mes-GC classifier applicable to multiple transcriptomic scenarios. Mes-GCs exhibit a distinct epigenomic landscape, and TEAD1 inhibition and combinatorial NUAK1 inhibition/cisplatin may represent potential targetable options.</description><subject>Chromatin</subject><subject>Cisplatin</subject><subject>Cisplatin - metabolism</subject><subject>Cisplatin - therapeutic use</subject><subject>CRISPR</subject><subject>Datasets</subject><subject>DNA methylation</subject><subject>Enhancer Elements, Genetic</subject><subject>Enhancers</subject><subject>Epigenesis, Genetic</subject><subject>Gastric cancer</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Genomes</subject><subject>Genomic analysis</subject><subject>Humans</subject><subject>Immunoprecipitation</subject><subject>Kinases</subject><subject>Medical prognosis</subject><subject>Medical research</subject><subject>Mesenchyme</subject><subject>Mutation</subject><subject>Patients</subject><subject>Prospective Studies</subject><subject>Protein Kinases - genetics</subject><subject>Repressor Proteins</subject><subject>Retrospective Studies</subject><subject>RNA editing</subject><subject>Stomach</subject><subject>Stomach Neoplasms - genetics</subject><subject>Transcriptomics</subject><subject>Transposase</subject><subject>Tumors</subject><issn>0017-5749</issn><issn>1468-3288</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kU2L1TAUhoMoznX0D7iQgBs3HfPdZCnD-AEDgug6JOlpp5c2rUk6cP-Ev9lcOiq4mFVOOM95z8eL0GtKrijl6v2wlWOcGkYYbThTQvMn6ECF0vWn9VN0IIS2jWyFuUAvcj4SQrQ29Dm64FLTVkp5QL--wbBNrizphCHeuRgg4TUt_TiNccBLj2fIEMPdaXZTU04r4MHlksaAww4nuAc3ZZw3f043eYUw9jUP6zhAXOYaTi52ObgVMq4RLi4NUJyfAN9vU4TkfG1XRsgv0bO-isGrh_cS_fh48_36c3P79dOX6w-3jedGl8ZIJoxzumeK0F4SrloIxjulpaDcS8I68MYbIwjoeh_dBdPWoxDTBd53kl-id7tuXfXnBrnYecwBpjooLFu2TGktGSVEVfTtf-hx2VKs01nWKkqE1O3jVNUiUhgpKsV2KqQl5wS9XdM4u3SylNizp3b31J49tbuntejNg_TmZ-j-lvwxsQJXO-Dn47-2jyj-Bk3Yr1c</recordid><startdate>20230201</startdate><enddate>20230201</enddate><creator>Ho, Shamaine Wei Ting</creator><creator>Sheng, Taotao</creator><creator>Xing, Manjie</creator><creator>Ooi, Wen Fong</creator><creator>Xu, Chang</creator><creator>Sundar, Raghav</creator><creator>Huang, Kie Kyon</creator><creator>Li, Zhimei</creator><creator>Kumar, Vikrant</creator><creator>Ramnarayanan, Kalpana</creator><creator>Zhu, Feng</creator><creator>Srivastava, Supriya</creator><creator>Isa, Zul Fazreen Bin Adam</creator><creator>Anene-Nzelu, Chukwuemeka George</creator><creator>Razavi-Mohseni, Milad</creator><creator>Shigaki, Dustin</creator><creator>Ma, Haoran</creator><creator>Tan, Angie Lay Keng</creator><creator>Ong, Xuewen</creator><creator>Lee, Ming Hui</creator><creator>Tay, Su Ting</creator><creator>Guo, Yu Amanda</creator><creator>Huang, Weitai</creator><creator>Li, Shang</creator><creator>Beer, Michael A.</creator><creator>Foo, Roger Sik Yin</creator><creator>Teh, Ming</creator><creator>Skanderup, Anders Jacobsen</creator><creator>Teh, Bin Tean</creator><creator>Tan, Patrick</creator><general>BMJ Publishing Group Ltd and British Society of Gastroenterology</general><general>BMJ Publishing Group LTD</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8AF</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>BTHHO</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-2595-0710</orcidid><orcidid>https://orcid.org/0000-0001-9423-1368</orcidid><orcidid>https://orcid.org/0000-0002-6052-3159</orcidid><orcidid>https://orcid.org/0000-0002-0179-8048</orcidid><orcidid>https://orcid.org/0000-0001-6030-9251</orcidid><orcidid>https://orcid.org/0000-0003-4104-8951</orcidid></search><sort><creationdate>20230201</creationdate><title>Regulatory enhancer profiling of mesenchymal-type gastric cancer reveals subtype-specific epigenomic landscapes and targetable vulnerabilities</title><author>Ho, Shamaine Wei Ting ; Sheng, Taotao ; Xing, Manjie ; Ooi, Wen Fong ; Xu, Chang ; Sundar, Raghav ; Huang, Kie Kyon ; Li, Zhimei ; Kumar, Vikrant ; Ramnarayanan, Kalpana ; Zhu, Feng ; Srivastava, Supriya ; Isa, Zul Fazreen Bin Adam ; Anene-Nzelu, Chukwuemeka George ; Razavi-Mohseni, Milad ; Shigaki, Dustin ; Ma, Haoran ; Tan, Angie Lay Keng ; Ong, Xuewen ; Lee, Ming Hui ; Tay, Su Ting ; Guo, Yu Amanda ; Huang, Weitai ; Li, Shang ; Beer, Michael A. ; Foo, Roger Sik Yin ; Teh, Ming ; Skanderup, Anders Jacobsen ; Teh, Bin Tean ; Tan, Patrick</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b398t-95249aa8f2601f50367ec9ba685413b502deb9b9940e82028dc9732809dc3fd53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Chromatin</topic><topic>Cisplatin</topic><topic>Cisplatin - metabolism</topic><topic>Cisplatin - therapeutic use</topic><topic>CRISPR</topic><topic>Datasets</topic><topic>DNA methylation</topic><topic>Enhancer Elements, Genetic</topic><topic>Enhancers</topic><topic>Epigenesis, Genetic</topic><topic>Gastric cancer</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Genomes</topic><topic>Genomic analysis</topic><topic>Humans</topic><topic>Immunoprecipitation</topic><topic>Kinases</topic><topic>Medical prognosis</topic><topic>Medical research</topic><topic>Mesenchyme</topic><topic>Mutation</topic><topic>Patients</topic><topic>Prospective Studies</topic><topic>Protein Kinases - genetics</topic><topic>Repressor Proteins</topic><topic>Retrospective Studies</topic><topic>RNA editing</topic><topic>Stomach</topic><topic>Stomach Neoplasms - genetics</topic><topic>Transcriptomics</topic><topic>Transposase</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ho, Shamaine Wei Ting</creatorcontrib><creatorcontrib>Sheng, Taotao</creatorcontrib><creatorcontrib>Xing, Manjie</creatorcontrib><creatorcontrib>Ooi, Wen Fong</creatorcontrib><creatorcontrib>Xu, Chang</creatorcontrib><creatorcontrib>Sundar, Raghav</creatorcontrib><creatorcontrib>Huang, Kie Kyon</creatorcontrib><creatorcontrib>Li, Zhimei</creatorcontrib><creatorcontrib>Kumar, Vikrant</creatorcontrib><creatorcontrib>Ramnarayanan, Kalpana</creatorcontrib><creatorcontrib>Zhu, Feng</creatorcontrib><creatorcontrib>Srivastava, Supriya</creatorcontrib><creatorcontrib>Isa, Zul Fazreen Bin Adam</creatorcontrib><creatorcontrib>Anene-Nzelu, Chukwuemeka George</creatorcontrib><creatorcontrib>Razavi-Mohseni, Milad</creatorcontrib><creatorcontrib>Shigaki, Dustin</creatorcontrib><creatorcontrib>Ma, Haoran</creatorcontrib><creatorcontrib>Tan, Angie Lay Keng</creatorcontrib><creatorcontrib>Ong, Xuewen</creatorcontrib><creatorcontrib>Lee, Ming Hui</creatorcontrib><creatorcontrib>Tay, Su Ting</creatorcontrib><creatorcontrib>Guo, Yu Amanda</creatorcontrib><creatorcontrib>Huang, Weitai</creatorcontrib><creatorcontrib>Li, Shang</creatorcontrib><creatorcontrib>Beer, Michael A.</creatorcontrib><creatorcontrib>Foo, Roger Sik Yin</creatorcontrib><creatorcontrib>Teh, Ming</creatorcontrib><creatorcontrib>Skanderup, Anders Jacobsen</creatorcontrib><creatorcontrib>Teh, Bin Tean</creatorcontrib><creatorcontrib>Tan, Patrick</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>STEM Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>BMJ Journals</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><jtitle>Gut</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ho, Shamaine Wei Ting</au><au>Sheng, Taotao</au><au>Xing, Manjie</au><au>Ooi, Wen Fong</au><au>Xu, Chang</au><au>Sundar, Raghav</au><au>Huang, Kie Kyon</au><au>Li, Zhimei</au><au>Kumar, Vikrant</au><au>Ramnarayanan, Kalpana</au><au>Zhu, Feng</au><au>Srivastava, Supriya</au><au>Isa, Zul Fazreen Bin Adam</au><au>Anene-Nzelu, Chukwuemeka George</au><au>Razavi-Mohseni, Milad</au><au>Shigaki, Dustin</au><au>Ma, Haoran</au><au>Tan, Angie Lay Keng</au><au>Ong, Xuewen</au><au>Lee, Ming Hui</au><au>Tay, Su Ting</au><au>Guo, Yu Amanda</au><au>Huang, Weitai</au><au>Li, Shang</au><au>Beer, Michael A.</au><au>Foo, Roger Sik Yin</au><au>Teh, Ming</au><au>Skanderup, Anders Jacobsen</au><au>Teh, Bin Tean</au><au>Tan, Patrick</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Regulatory enhancer profiling of mesenchymal-type gastric cancer reveals subtype-specific epigenomic landscapes and targetable vulnerabilities</atitle><jtitle>Gut</jtitle><stitle>Gut</stitle><addtitle>Gut</addtitle><date>2023-02-01</date><risdate>2023</risdate><volume>72</volume><issue>2</issue><spage>226</spage><epage>241</epage><pages>226-241</pages><issn>0017-5749</issn><eissn>1468-3288</eissn><abstract>ObjectiveGastric cancer (GC) comprises multiple molecular subtypes. Recent studies have highlighted mesenchymal-subtype GC (Mes-GC) as a clinically aggressive subtype with few treatment options. Combining multiple studies, we derived and applied a consensus Mes-GC classifier to define the Mes-GC enhancer landscape revealing disease vulnerabilities.DesignTranscriptomic profiles of ~1000 primary GCs and cell lines were analysed to derive a consensus Mes-GC classifier. Clinical and genomic associations were performed across >1200 patients with GC. Genome-wide epigenomic profiles (H3K27ac, H3K4me1 and assay for transposase-accessible chromatin with sequencing (ATAC-seq)) of 49 primary GCs and GC cell lines were generated to identify Mes-GC-specific enhancer landscapes. Upstream regulators and downstream targets of Mes-GC enhancers were interrogated using chromatin immunoprecipitation followed by sequencing (ChIP-seq), RNA sequencing, CRISPR/Cas9 editing, functional assays and pharmacological inhibition.ResultsWe identified and validated a 993-gene cancer-cell intrinsic Mes-GC classifier applicable to retrospective cohorts or prospective single samples. Multicohort analysis of Mes-GCs confirmed associations with poor patient survival, therapy resistance and few targetable genomic alterations. Analysis of enhancer profiles revealed a distinctive Mes-GC epigenomic landscape, with TEAD1 as a master regulator of Mes-GC enhancers and Mes-GCs exhibiting preferential sensitivity to TEAD1 pharmacological inhibition. Analysis of Mes-GC super-enhancers also highlighted NUAK1 kinase as a downstream target, with synergistic effects observed between NUAK1 inhibition and cisplatin treatment.ConclusionOur results establish a consensus Mes-GC classifier applicable to multiple transcriptomic scenarios. Mes-GCs exhibit a distinct epigenomic landscape, and TEAD1 inhibition and combinatorial NUAK1 inhibition/cisplatin may represent potential targetable options.</abstract><cop>England</cop><pub>BMJ Publishing Group Ltd and British Society of Gastroenterology</pub><pmid>35817555</pmid><doi>10.1136/gutjnl-2021-326483</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0002-2595-0710</orcidid><orcidid>https://orcid.org/0000-0001-9423-1368</orcidid><orcidid>https://orcid.org/0000-0002-6052-3159</orcidid><orcidid>https://orcid.org/0000-0002-0179-8048</orcidid><orcidid>https://orcid.org/0000-0001-6030-9251</orcidid><orcidid>https://orcid.org/0000-0003-4104-8951</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0017-5749 |
| ispartof | Gut, 2023-02, Vol.72 (2), p.226-241 |
| issn | 0017-5749 1468-3288 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2688521006 |
| source | MEDLINE; PubMed Central |
| subjects | Chromatin Cisplatin Cisplatin - metabolism Cisplatin - therapeutic use CRISPR Datasets DNA methylation Enhancer Elements, Genetic Enhancers Epigenesis, Genetic Gastric cancer Gene expression Gene Expression Regulation, Neoplastic Genomes Genomic analysis Humans Immunoprecipitation Kinases Medical prognosis Medical research Mesenchyme Mutation Patients Prospective Studies Protein Kinases - genetics Repressor Proteins Retrospective Studies RNA editing Stomach Stomach Neoplasms - genetics Transcriptomics Transposase Tumors |
| title | Regulatory enhancer profiling of mesenchymal-type gastric cancer reveals subtype-specific epigenomic landscapes and targetable vulnerabilities |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-19T20%3A04%3A31IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Regulatory%20enhancer%20profiling%20of%20mesenchymal-type%20gastric%20cancer%20reveals%20subtype-specific%20epigenomic%20landscapes%20and%20targetable%20vulnerabilities&rft.jtitle=Gut&rft.au=Ho,%20Shamaine%20Wei%20Ting&rft.date=2023-02-01&rft.volume=72&rft.issue=2&rft.spage=226&rft.epage=241&rft.pages=226-241&rft.issn=0017-5749&rft.eissn=1468-3288&rft_id=info:doi/10.1136/gutjnl-2021-326483&rft_dat=%3Cproquest_cross%3E2688521006%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2688054954&rft_id=info:pmid/35817555&rfr_iscdi=true |