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Molecular dissection of CRC primary tumors and their matched liver metastases reveals critical role of immune microenvironment, EMT and angiogenesis in cancer metastasis
Metastasis is the primary cause of cancer mortality. The primary tumors of colorectal cancer (CRC) often metastasize to the liver. In this study, we have collected 122 samples from 45 CRC patients. Among them, 32 patients have primary tumors, adjacent normal tissues, and matched liver metastases. Th...
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Published in: | Scientific reports 2020-07, Vol.10 (1), p.10725-10725, Article 10725 |
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description | Metastasis is the primary cause of cancer mortality. The primary tumors of colorectal cancer (CRC) often metastasize to the liver. In this study, we have collected 122 samples from 45 CRC patients. Among them, 32 patients have primary tumors, adjacent normal tissues, and matched liver metastases. Thirteen patients have primary tumors without distant metastasis and matched normal tissues. Characterization of these samples was conducted by whole-exome and RNA sequencing and SNP6.0 analysis. Our results revealed no significant difference in genetic alterations including common oncogenic mutations, whole genome mutations and copy number variations between primary and metastatic tumors. We then assembled gene co-expression networks and identified metastasis-correlated gene networks of immune-suppression, epithelial–mesenchymal transition (EMT) and angiogenesis as the key events and potentially synergistic drivers associated with CRC metastasis. Further independent cohort validation using published datasets has verified that these specific gene networks are up regulated throughout the tumor progression. The gene networks of EMT, angiogenesis, immune-suppression and T cell exhaustion are closely correlated with the poor patient outcome and intrinsic anti-PD-1 resistance. These results offer insights of combinational strategy for the treatment of metastatic CRC. |
doi_str_mv | 10.1038/s41598-020-67842-5 |
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The primary tumors of colorectal cancer (CRC) often metastasize to the liver. In this study, we have collected 122 samples from 45 CRC patients. Among them, 32 patients have primary tumors, adjacent normal tissues, and matched liver metastases. Thirteen patients have primary tumors without distant metastasis and matched normal tissues. Characterization of these samples was conducted by whole-exome and RNA sequencing and SNP6.0 analysis. Our results revealed no significant difference in genetic alterations including common oncogenic mutations, whole genome mutations and copy number variations between primary and metastatic tumors. We then assembled gene co-expression networks and identified metastasis-correlated gene networks of immune-suppression, epithelial–mesenchymal transition (EMT) and angiogenesis as the key events and potentially synergistic drivers associated with CRC metastasis. Further independent cohort validation using published datasets has verified that these specific gene networks are up regulated throughout the tumor progression. The gene networks of EMT, angiogenesis, immune-suppression and T cell exhaustion are closely correlated with the poor patient outcome and intrinsic anti-PD-1 resistance. These results offer insights of combinational strategy for the treatment of metastatic CRC.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-020-67842-5</identifier><identifier>PMID: 32612211</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/114 ; 631/337 ; 631/67 ; Angiogenesis ; Biomarkers, Tumor - genetics ; Cancer ; Cohort Studies ; Colorectal cancer ; Colorectal carcinoma ; Colorectal Neoplasms - blood supply ; Colorectal Neoplasms - genetics ; Colorectal Neoplasms - pathology ; Copy number ; DNA Copy Number Variations ; Epithelial-Mesenchymal Transition ; Follow-Up Studies ; Gene Expression Regulation, Neoplastic ; Gene Regulatory Networks ; Genomes ; Humanities and Social Sciences ; Humans ; Liver ; Liver Neoplasms - blood supply ; Liver Neoplasms - genetics ; Liver Neoplasms - secondary ; Lymphocytes T ; Mesenchyme ; Metastases ; Metastasis ; multidisciplinary ; Mutation ; Neovascularization, Pathologic ; PD-1 protein ; Prognosis ; Ribonucleic acid ; RNA ; Science ; Science (multidisciplinary) ; Survival Rate ; Tumor Microenvironment - genetics ; Tumor Microenvironment - immunology ; Tumors</subject><ispartof>Scientific reports, 2020-07, Vol.10 (1), p.10725-10725, Article 10725</ispartof><rights>The Author(s) 2020</rights><rights>The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-44b71b0bc1128f7a4a7a5902d64d28f0b70cc0d10668d11c5731ac089d45d23a3</citedby><cites>FETCH-LOGICAL-c474t-44b71b0bc1128f7a4a7a5902d64d28f0b70cc0d10668d11c5731ac089d45d23a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/2419205034/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2419205034?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27924,27925,37012,37013,44590,53791,53793,75126</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32612211$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Jiangang</creatorcontrib><creatorcontrib>Cho, Yong Beom</creatorcontrib><creatorcontrib>Hong, Hye Kyung</creatorcontrib><creatorcontrib>Wu, Song</creatorcontrib><creatorcontrib>Ebert, Philip J.</creatorcontrib><creatorcontrib>Bray, Steven M.</creatorcontrib><creatorcontrib>Wong, Swee Seong</creatorcontrib><creatorcontrib>Ting, Jason C.</creatorcontrib><creatorcontrib>Calley, John N.</creatorcontrib><creatorcontrib>Whittington, Catherine F.</creatorcontrib><creatorcontrib>Bhagwat, Shripad V.</creatorcontrib><creatorcontrib>Reinhard, Christoph</creatorcontrib><creatorcontrib>Wild, Robert</creatorcontrib><creatorcontrib>Nam, Do-Hyun</creatorcontrib><creatorcontrib>Aggarwal, Amit</creatorcontrib><creatorcontrib>Lee, Woo Yong</creatorcontrib><creatorcontrib>Peng, Sheng-Bin</creatorcontrib><title>Molecular dissection of CRC primary tumors and their matched liver metastases reveals critical role of immune microenvironment, EMT and angiogenesis in cancer metastasis</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>Metastasis is the primary cause of cancer mortality. The primary tumors of colorectal cancer (CRC) often metastasize to the liver. In this study, we have collected 122 samples from 45 CRC patients. Among them, 32 patients have primary tumors, adjacent normal tissues, and matched liver metastases. Thirteen patients have primary tumors without distant metastasis and matched normal tissues. Characterization of these samples was conducted by whole-exome and RNA sequencing and SNP6.0 analysis. Our results revealed no significant difference in genetic alterations including common oncogenic mutations, whole genome mutations and copy number variations between primary and metastatic tumors. We then assembled gene co-expression networks and identified metastasis-correlated gene networks of immune-suppression, epithelial–mesenchymal transition (EMT) and angiogenesis as the key events and potentially synergistic drivers associated with CRC metastasis. Further independent cohort validation using published datasets has verified that these specific gene networks are up regulated throughout the tumor progression. The gene networks of EMT, angiogenesis, immune-suppression and T cell exhaustion are closely correlated with the poor patient outcome and intrinsic anti-PD-1 resistance. These results offer insights of combinational strategy for the treatment of metastatic CRC.</description><subject>631/114</subject><subject>631/337</subject><subject>631/67</subject><subject>Angiogenesis</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Cancer</subject><subject>Cohort Studies</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Colorectal Neoplasms - blood supply</subject><subject>Colorectal Neoplasms - genetics</subject><subject>Colorectal Neoplasms - pathology</subject><subject>Copy number</subject><subject>DNA Copy Number Variations</subject><subject>Epithelial-Mesenchymal Transition</subject><subject>Follow-Up Studies</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene Regulatory Networks</subject><subject>Genomes</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Liver</subject><subject>Liver Neoplasms - blood supply</subject><subject>Liver Neoplasms - genetics</subject><subject>Liver Neoplasms - secondary</subject><subject>Lymphocytes T</subject><subject>Mesenchyme</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>multidisciplinary</subject><subject>Mutation</subject><subject>Neovascularization, Pathologic</subject><subject>PD-1 protein</subject><subject>Prognosis</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Survival Rate</subject><subject>Tumor Microenvironment - genetics</subject><subject>Tumor Microenvironment - immunology</subject><subject>Tumors</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><recordid>eNp9kltrFDEUxwdRbKn9Aj5IwBcfHHtym8uLIEu9QEuh1OeQSc7upkySmsws-JH8lmYv1rUPhkBu__PLuVXVawofKPDuIgsq-64GBnXTdoLV8ll1ykDImnHGnh_tT6rznO-hDMl6QfuX1QlnDWWM0tPq13Uc0cyjTsS6nNFMLgYSl2RxuyAPyXmdfpJp9jFlooMl0xpdIl5PZo2WjG6D5YSTzmViJgk3qMdMTHKTM3okqeC3OOf9HJB4Z1LEsHEpBo9hek8ur-92YB1WLq4wYHaZuECMDuaI7fKr6sWyoPH8sJ5V3z9f3i2-1lc3X74tPl3VRrRiqoUYWjrAYChl3bLVQrda9sBsI2y5gKEFY8BSaJrOUmpky6k20PVWSMu45mfVxz33YR48WlO8THpUh1yoqJ369yW4tVrFjWo5BxBQAO8OgBR_zJgn5V02OI46YJyzYqUGLaW8E0X69on0Ps4plPB2KgYS-FbF9qqSu5wTLh-doaC2zaD2zaBKM6hdMyhZjN4ch_Fo8qf0RcD3glyewgrT37__g_0NpA_DMQ</recordid><startdate>20200701</startdate><enddate>20200701</enddate><creator>Liu, Jiangang</creator><creator>Cho, Yong Beom</creator><creator>Hong, Hye Kyung</creator><creator>Wu, Song</creator><creator>Ebert, Philip J.</creator><creator>Bray, Steven M.</creator><creator>Wong, Swee Seong</creator><creator>Ting, Jason C.</creator><creator>Calley, John N.</creator><creator>Whittington, Catherine F.</creator><creator>Bhagwat, Shripad V.</creator><creator>Reinhard, Christoph</creator><creator>Wild, Robert</creator><creator>Nam, Do-Hyun</creator><creator>Aggarwal, Amit</creator><creator>Lee, Woo Yong</creator><creator>Peng, Sheng-Bin</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><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>88A</scope><scope>88E</scope><scope>88I</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>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>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20200701</creationdate><title>Molecular dissection of CRC primary tumors and their matched liver metastases reveals critical role of immune microenvironment, EMT and angiogenesis in cancer metastasis</title><author>Liu, Jiangang ; Cho, Yong Beom ; Hong, Hye Kyung ; Wu, Song ; Ebert, Philip J. ; Bray, Steven M. ; Wong, Swee Seong ; Ting, Jason C. ; Calley, John N. ; Whittington, Catherine F. ; Bhagwat, Shripad V. ; Reinhard, Christoph ; Wild, Robert ; Nam, Do-Hyun ; Aggarwal, Amit ; Lee, Woo Yong ; Peng, Sheng-Bin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c474t-44b71b0bc1128f7a4a7a5902d64d28f0b70cc0d10668d11c5731ac089d45d23a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>631/114</topic><topic>631/337</topic><topic>631/67</topic><topic>Angiogenesis</topic><topic>Biomarkers, Tumor - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, Jiangang</au><au>Cho, Yong Beom</au><au>Hong, Hye Kyung</au><au>Wu, Song</au><au>Ebert, Philip J.</au><au>Bray, Steven M.</au><au>Wong, Swee Seong</au><au>Ting, Jason C.</au><au>Calley, John N.</au><au>Whittington, Catherine F.</au><au>Bhagwat, Shripad V.</au><au>Reinhard, Christoph</au><au>Wild, Robert</au><au>Nam, Do-Hyun</au><au>Aggarwal, Amit</au><au>Lee, Woo Yong</au><au>Peng, Sheng-Bin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Molecular dissection of CRC primary tumors and their matched liver metastases reveals critical role of immune microenvironment, EMT and angiogenesis in cancer metastasis</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2020-07-01</date><risdate>2020</risdate><volume>10</volume><issue>1</issue><spage>10725</spage><epage>10725</epage><pages>10725-10725</pages><artnum>10725</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>Metastasis is the primary cause of cancer mortality. The primary tumors of colorectal cancer (CRC) often metastasize to the liver. In this study, we have collected 122 samples from 45 CRC patients. Among them, 32 patients have primary tumors, adjacent normal tissues, and matched liver metastases. Thirteen patients have primary tumors without distant metastasis and matched normal tissues. Characterization of these samples was conducted by whole-exome and RNA sequencing and SNP6.0 analysis. Our results revealed no significant difference in genetic alterations including common oncogenic mutations, whole genome mutations and copy number variations between primary and metastatic tumors. We then assembled gene co-expression networks and identified metastasis-correlated gene networks of immune-suppression, epithelial–mesenchymal transition (EMT) and angiogenesis as the key events and potentially synergistic drivers associated with CRC metastasis. Further independent cohort validation using published datasets has verified that these specific gene networks are up regulated throughout the tumor progression. The gene networks of EMT, angiogenesis, immune-suppression and T cell exhaustion are closely correlated with the poor patient outcome and intrinsic anti-PD-1 resistance. These results offer insights of combinational strategy for the treatment of metastatic CRC.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>32612211</pmid><doi>10.1038/s41598-020-67842-5</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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subjects | 631/114 631/337 631/67 Angiogenesis Biomarkers, Tumor - genetics Cancer Cohort Studies Colorectal cancer Colorectal carcinoma Colorectal Neoplasms - blood supply Colorectal Neoplasms - genetics Colorectal Neoplasms - pathology Copy number DNA Copy Number Variations Epithelial-Mesenchymal Transition Follow-Up Studies Gene Expression Regulation, Neoplastic Gene Regulatory Networks Genomes Humanities and Social Sciences Humans Liver Liver Neoplasms - blood supply Liver Neoplasms - genetics Liver Neoplasms - secondary Lymphocytes T Mesenchyme Metastases Metastasis multidisciplinary Mutation Neovascularization, Pathologic PD-1 protein Prognosis Ribonucleic acid RNA Science Science (multidisciplinary) Survival Rate Tumor Microenvironment - genetics Tumor Microenvironment - immunology Tumors |
title | Molecular dissection of CRC primary tumors and their matched liver metastases reveals critical role of immune microenvironment, EMT and angiogenesis in cancer metastasis |
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