Novel targets identified by integrated cancer-stromal interactome analysis of pancreatic adenocarcinoma
The pancreatic cancer microenvironment is crucial in cancer development, progression and drug resistance. Cancer-stromal interactions have been recognized as important targets for cancer therapy. However, identifying relevant and druggable cancer-stromal interactions is challenging due to the lack o...
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| Veröffentlicht in: | Cancer letters 2020-01, Vol.469, p.217-227 |
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| creator | Hiroshima, Yukihiko Kasajima, Rika Kimura, Yayoi Komura, Daisuke Ishikawa, Shumpei Ichikawa, Yasushi Bouvet, Michael Yamamoto, Naoto Oshima, Takashi Morinaga, Soichiro Singh, Shree Ram Hoffman, Robert M. Endo, Itaru Miyagi, Yohei |
| description | The pancreatic cancer microenvironment is crucial in cancer development, progression and drug resistance. Cancer-stromal interactions have been recognized as important targets for cancer therapy. However, identifying relevant and druggable cancer-stromal interactions is challenging due to the lack of quantitative methods to analyze the whole cancer-stromal interactome. Here we studied 14 resected pancreatic cancer specimens (8 pancreatic adenocarcinoma (PDAC) patients as a cancer group and 6 intraductal papillary-mucinous adenoma (IPMA) patients as a control). Shotgun proteomics of the stromal lesion dissected with laser captured microdissection (LCM) was performed, and identified 102 differentially expressed proteins in pancreatic cancer stroma. Next, we obtained gene expression data in human pancreatic cancer and normal pancreatic tissue from The Cancer Genome Atlas database (n = 169) and The Genotype-Tissue Expression database (n = 197), and identified 1435 genes, which were differentially expressed in pancreatic cancer cells. To identify relevant and druggable cancer-stromal-interaction targets, we applied these datasets to our in-house ligand-receptor database. Finally, we identified 9 key genes and 8 key cancer-stromal-interaction targets for PDAC patients. Furthermore, we examined FN1 and ITGA3 protein expression in pancreatic cancer tissues using tissue microarrays (TMAs) of 271 PDAC cases, and demonstrated that FN1-ITGA3 had unfavorable prognostic impact for PDAC patients.
•Performed a shotgun proteomic analysis using dissected stromal areas of PDAC tissues.•Identified differentially-expressed (DE) proteins in PDAC stroma.•Identified crucial and potentially druggable cancer-stromal interactions in PDAC.•Identified 9 key genes and 8 key cancer-stromal-interaction targets for PDAC patients.•FN1-ITGA3 and FN1-ITGA5 have unfavorable prognostic impact for PDAC patients. |
| doi_str_mv | 10.1016/j.canlet.2019.10.031 |
| format | Article |
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•Performed a shotgun proteomic analysis using dissected stromal areas of PDAC tissues.•Identified differentially-expressed (DE) proteins in PDAC stroma.•Identified crucial and potentially druggable cancer-stromal interactions in PDAC.•Identified 9 key genes and 8 key cancer-stromal-interaction targets for PDAC patients.•FN1-ITGA3 and FN1-ITGA5 have unfavorable prognostic impact for PDAC patients.</description><identifier>ISSN: 0304-3835</identifier><identifier>EISSN: 1872-7980</identifier><identifier>DOI: 10.1016/j.canlet.2019.10.031</identifier><language>eng</language><publisher>Clare: Elsevier B.V</publisher><subject>Adenocarcinoma ; Adenoma ; Bioinformatics ; Cancer-stromal interaction ; Cell adhesion & migration ; Collagen ; DNA microarrays ; Drug resistance ; Ethanol ; Gene expression ; Genes ; Genomes ; Genotypes ; Ligands ; Lymphatic system ; Medical prognosis ; Melanoma ; Metastasis ; Pancreatic cancer ; Pancreatitis ; Proteomics ; Stroma ; Tissues ; Tumors</subject><ispartof>Cancer letters, 2020-01, Vol.469, p.217-227</ispartof><rights>2019</rights><rights>Copyright Elsevier Limited Jan 28, 2020</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c433t-d0c009260ffdea26cc31e092f3c4b6f2ef8a23f0e47e4e8c55f634d1350ef2ba3</citedby><cites>FETCH-LOGICAL-c433t-d0c009260ffdea26cc31e092f3c4b6f2ef8a23f0e47e4e8c55f634d1350ef2ba3</cites><orcidid>0000-0001-6545-583X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0304383519305348$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids></links><search><creatorcontrib>Hiroshima, Yukihiko</creatorcontrib><creatorcontrib>Kasajima, Rika</creatorcontrib><creatorcontrib>Kimura, Yayoi</creatorcontrib><creatorcontrib>Komura, Daisuke</creatorcontrib><creatorcontrib>Ishikawa, Shumpei</creatorcontrib><creatorcontrib>Ichikawa, Yasushi</creatorcontrib><creatorcontrib>Bouvet, Michael</creatorcontrib><creatorcontrib>Yamamoto, Naoto</creatorcontrib><creatorcontrib>Oshima, Takashi</creatorcontrib><creatorcontrib>Morinaga, Soichiro</creatorcontrib><creatorcontrib>Singh, Shree Ram</creatorcontrib><creatorcontrib>Hoffman, Robert M.</creatorcontrib><creatorcontrib>Endo, Itaru</creatorcontrib><creatorcontrib>Miyagi, Yohei</creatorcontrib><title>Novel targets identified by integrated cancer-stromal interactome analysis of pancreatic adenocarcinoma</title><title>Cancer letters</title><description>The pancreatic cancer microenvironment is crucial in cancer development, progression and drug resistance. Cancer-stromal interactions have been recognized as important targets for cancer therapy. However, identifying relevant and druggable cancer-stromal interactions is challenging due to the lack of quantitative methods to analyze the whole cancer-stromal interactome. Here we studied 14 resected pancreatic cancer specimens (8 pancreatic adenocarcinoma (PDAC) patients as a cancer group and 6 intraductal papillary-mucinous adenoma (IPMA) patients as a control). Shotgun proteomics of the stromal lesion dissected with laser captured microdissection (LCM) was performed, and identified 102 differentially expressed proteins in pancreatic cancer stroma. Next, we obtained gene expression data in human pancreatic cancer and normal pancreatic tissue from The Cancer Genome Atlas database (n = 169) and The Genotype-Tissue Expression database (n = 197), and identified 1435 genes, which were differentially expressed in pancreatic cancer cells. To identify relevant and druggable cancer-stromal-interaction targets, we applied these datasets to our in-house ligand-receptor database. Finally, we identified 9 key genes and 8 key cancer-stromal-interaction targets for PDAC patients. Furthermore, we examined FN1 and ITGA3 protein expression in pancreatic cancer tissues using tissue microarrays (TMAs) of 271 PDAC cases, and demonstrated that FN1-ITGA3 had unfavorable prognostic impact for PDAC patients.
•Performed a shotgun proteomic analysis using dissected stromal areas of PDAC tissues.•Identified differentially-expressed (DE) proteins in PDAC stroma.•Identified crucial and potentially druggable cancer-stromal interactions in PDAC.•Identified 9 key genes and 8 key cancer-stromal-interaction targets for PDAC patients.•FN1-ITGA3 and FN1-ITGA5 have unfavorable prognostic impact for PDAC patients.</description><subject>Adenocarcinoma</subject><subject>Adenoma</subject><subject>Bioinformatics</subject><subject>Cancer-stromal interaction</subject><subject>Cell adhesion & migration</subject><subject>Collagen</subject><subject>DNA microarrays</subject><subject>Drug resistance</subject><subject>Ethanol</subject><subject>Gene expression</subject><subject>Genes</subject><subject>Genomes</subject><subject>Genotypes</subject><subject>Ligands</subject><subject>Lymphatic system</subject><subject>Medical prognosis</subject><subject>Melanoma</subject><subject>Metastasis</subject><subject>Pancreatic cancer</subject><subject>Pancreatitis</subject><subject>Proteomics</subject><subject>Stroma</subject><subject>Tissues</subject><subject>Tumors</subject><issn>0304-3835</issn><issn>1872-7980</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNp9kEtLAzEUhYMoWKv_wEXA9Yw3j3l0I0jxBUU3ug5p5qZkmE5qkhb6700d125uuCf3nJt8hNwyKBmw-r4vjR4HTCUHtshSCYKdkRlrG140ixbOyQwEyEK0orokVzH2AFDJppqRzbs_4ECTDhtMkboOx-Ssw46uj9SNCTdBp9zlBQZDEVPwWz383gRtkt8i1aMejtFF6i3d5bGAOjlDdY7yRgfjxmy5JhdWDxFv_s45-Xp--ly-FquPl7fl46owUohUdGAAFrwGazvUvDZGMMyCFUaua8vRtpoLCygblNiaqrK1kB0TFaDlay3m5G7K3QX_vceYVO_3Ib8wKi44ywRkrnMipykTfIwBrdoFt9XhqBioE1LVqwmpOiE9qRlptj1MNsw_ODgMKhqHGUznApqkOu_-D_gB9SuD1w</recordid><startdate>20200128</startdate><enddate>20200128</enddate><creator>Hiroshima, Yukihiko</creator><creator>Kasajima, Rika</creator><creator>Kimura, Yayoi</creator><creator>Komura, Daisuke</creator><creator>Ishikawa, Shumpei</creator><creator>Ichikawa, Yasushi</creator><creator>Bouvet, Michael</creator><creator>Yamamoto, Naoto</creator><creator>Oshima, Takashi</creator><creator>Morinaga, Soichiro</creator><creator>Singh, Shree Ram</creator><creator>Hoffman, Robert M.</creator><creator>Endo, Itaru</creator><creator>Miyagi, Yohei</creator><general>Elsevier B.V</general><general>Elsevier Limited</general><scope>AAYXX</scope><scope>CITATION</scope><scope>7TO</scope><scope>7U9</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><orcidid>https://orcid.org/0000-0001-6545-583X</orcidid></search><sort><creationdate>20200128</creationdate><title>Novel targets identified by integrated cancer-stromal interactome analysis of pancreatic adenocarcinoma</title><author>Hiroshima, Yukihiko ; Kasajima, Rika ; Kimura, Yayoi ; Komura, Daisuke ; Ishikawa, Shumpei ; Ichikawa, Yasushi ; Bouvet, Michael ; Yamamoto, Naoto ; Oshima, Takashi ; Morinaga, Soichiro ; Singh, Shree Ram ; Hoffman, Robert M. ; Endo, Itaru ; Miyagi, Yohei</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c433t-d0c009260ffdea26cc31e092f3c4b6f2ef8a23f0e47e4e8c55f634d1350ef2ba3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Adenocarcinoma</topic><topic>Adenoma</topic><topic>Bioinformatics</topic><topic>Cancer-stromal interaction</topic><topic>Cell adhesion & migration</topic><topic>Collagen</topic><topic>DNA microarrays</topic><topic>Drug resistance</topic><topic>Ethanol</topic><topic>Gene expression</topic><topic>Genes</topic><topic>Genomes</topic><topic>Genotypes</topic><topic>Ligands</topic><topic>Lymphatic system</topic><topic>Medical prognosis</topic><topic>Melanoma</topic><topic>Metastasis</topic><topic>Pancreatic cancer</topic><topic>Pancreatitis</topic><topic>Proteomics</topic><topic>Stroma</topic><topic>Tissues</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hiroshima, Yukihiko</creatorcontrib><creatorcontrib>Kasajima, Rika</creatorcontrib><creatorcontrib>Kimura, Yayoi</creatorcontrib><creatorcontrib>Komura, Daisuke</creatorcontrib><creatorcontrib>Ishikawa, Shumpei</creatorcontrib><creatorcontrib>Ichikawa, Yasushi</creatorcontrib><creatorcontrib>Bouvet, Michael</creatorcontrib><creatorcontrib>Yamamoto, Naoto</creatorcontrib><creatorcontrib>Oshima, Takashi</creatorcontrib><creatorcontrib>Morinaga, Soichiro</creatorcontrib><creatorcontrib>Singh, Shree Ram</creatorcontrib><creatorcontrib>Hoffman, Robert M.</creatorcontrib><creatorcontrib>Endo, Itaru</creatorcontrib><creatorcontrib>Miyagi, Yohei</creatorcontrib><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><jtitle>Cancer letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hiroshima, Yukihiko</au><au>Kasajima, Rika</au><au>Kimura, Yayoi</au><au>Komura, Daisuke</au><au>Ishikawa, Shumpei</au><au>Ichikawa, Yasushi</au><au>Bouvet, Michael</au><au>Yamamoto, Naoto</au><au>Oshima, Takashi</au><au>Morinaga, Soichiro</au><au>Singh, Shree Ram</au><au>Hoffman, Robert M.</au><au>Endo, Itaru</au><au>Miyagi, Yohei</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Novel targets identified by integrated cancer-stromal interactome analysis of pancreatic adenocarcinoma</atitle><jtitle>Cancer letters</jtitle><date>2020-01-28</date><risdate>2020</risdate><volume>469</volume><spage>217</spage><epage>227</epage><pages>217-227</pages><issn>0304-3835</issn><eissn>1872-7980</eissn><abstract>The pancreatic cancer microenvironment is crucial in cancer development, progression and drug resistance. Cancer-stromal interactions have been recognized as important targets for cancer therapy. However, identifying relevant and druggable cancer-stromal interactions is challenging due to the lack of quantitative methods to analyze the whole cancer-stromal interactome. Here we studied 14 resected pancreatic cancer specimens (8 pancreatic adenocarcinoma (PDAC) patients as a cancer group and 6 intraductal papillary-mucinous adenoma (IPMA) patients as a control). Shotgun proteomics of the stromal lesion dissected with laser captured microdissection (LCM) was performed, and identified 102 differentially expressed proteins in pancreatic cancer stroma. Next, we obtained gene expression data in human pancreatic cancer and normal pancreatic tissue from The Cancer Genome Atlas database (n = 169) and The Genotype-Tissue Expression database (n = 197), and identified 1435 genes, which were differentially expressed in pancreatic cancer cells. To identify relevant and druggable cancer-stromal-interaction targets, we applied these datasets to our in-house ligand-receptor database. Finally, we identified 9 key genes and 8 key cancer-stromal-interaction targets for PDAC patients. Furthermore, we examined FN1 and ITGA3 protein expression in pancreatic cancer tissues using tissue microarrays (TMAs) of 271 PDAC cases, and demonstrated that FN1-ITGA3 had unfavorable prognostic impact for PDAC patients.
•Performed a shotgun proteomic analysis using dissected stromal areas of PDAC tissues.•Identified differentially-expressed (DE) proteins in PDAC stroma.•Identified crucial and potentially druggable cancer-stromal interactions in PDAC.•Identified 9 key genes and 8 key cancer-stromal-interaction targets for PDAC patients.•FN1-ITGA3 and FN1-ITGA5 have unfavorable prognostic impact for PDAC patients.</abstract><cop>Clare</cop><pub>Elsevier B.V</pub><doi>10.1016/j.canlet.2019.10.031</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0001-6545-583X</orcidid></addata></record> |
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| subjects | Adenocarcinoma Adenoma Bioinformatics Cancer-stromal interaction Cell adhesion & migration Collagen DNA microarrays Drug resistance Ethanol Gene expression Genes Genomes Genotypes Ligands Lymphatic system Medical prognosis Melanoma Metastasis Pancreatic cancer Pancreatitis Proteomics Stroma Tissues Tumors |
| title | Novel targets identified by integrated cancer-stromal interactome analysis of pancreatic adenocarcinoma |
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