TLR2 activation promotes tumour growth and associates with patient survival and chemotherapy response in pancreatic ductal adenocarcinoma
Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis, and is plagued by a paucity of targeted treatment options and tumour resistance to chemotherapeutics. The causal link between chronic inflammation and PDAC suggests that molecular regulators of the immune system promote disease...
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| Veröffentlicht in: | Oncogene 2021-10, Vol.40 (41), p.6007-6022 |
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| creator | Lundy, Joanne Gearing, Linden J. Gao, Hugh West, Alison C. McLeod, Louise Deswaerte, Virginie Yu, Liang Porazinski, Sean Pajic, Marina Hertzog, Paul J. Croagh, Daniel Jenkins, Brendan J. |
| description | Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis, and is plagued by a paucity of targeted treatment options and tumour resistance to chemotherapeutics. The causal link between chronic inflammation and PDAC suggests that molecular regulators of the immune system promote disease pathogenesis and/or therapeutic resistance, yet their identity is unclear. Here, we couple endoscopic ultrasound-guided fine-needle aspiration, which captures tumour biopsies from all stages, with whole transcriptome profiling of PDAC patient primary tumours to reveal enrichment of the innate immune Toll-like receptor 2 (TLR2) molecular pathway. Augmented TLR2 expression associated with a 4-gene “TLR2 activation” signature, and was prognostic for survival and predictive for gemcitabine-based chemoresistance. Furthermore, antibody-mediated anti-TLR2 therapy suppressed the growth of human PDAC tumour xenografts, independent of a functional immune system. Our results support TLR2-based therapeutic targeting for precision medicine in PDAC, with further clinical utility that TLR2 activation is prognostic and predictive for chemoresponsiveness. |
| doi_str_mv | 10.1038/s41388-021-01992-2 |
| format | Article |
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The causal link between chronic inflammation and PDAC suggests that molecular regulators of the immune system promote disease pathogenesis and/or therapeutic resistance, yet their identity is unclear. Here, we couple endoscopic ultrasound-guided fine-needle aspiration, which captures tumour biopsies from all stages, with whole transcriptome profiling of PDAC patient primary tumours to reveal enrichment of the innate immune Toll-like receptor 2 (TLR2) molecular pathway. Augmented TLR2 expression associated with a 4-gene “TLR2 activation” signature, and was prognostic for survival and predictive for gemcitabine-based chemoresistance. Furthermore, antibody-mediated anti-TLR2 therapy suppressed the growth of human PDAC tumour xenografts, independent of a functional immune system. Our results support TLR2-based therapeutic targeting for precision medicine in PDAC, with further clinical utility that TLR2 activation is prognostic and predictive for chemoresponsiveness.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/s41388-021-01992-2</identifier><identifier>PMID: 34400766</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>38/1 ; 38/23 ; 38/39 ; 38/77 ; 38/91 ; 45 ; 631/250/262 ; 631/67/1059/2326 ; 631/67/1059/602 ; 631/67/1504/1713 ; 64/60 ; 82/51 ; Adenocarcinoma ; Animals ; Apoptosis ; Biopsy ; Cancer ; Carcinoma, Pancreatic Ductal - drug therapy ; Carcinoma, Pancreatic Ductal - metabolism ; Carcinoma, Pancreatic Ductal - pathology ; Care and treatment ; Cell Biology ; Cell Growth Processes - drug effects ; Cell Growth Processes - physiology ; Cell Line, Tumor ; Cellular signal transduction ; Chemoresistance ; Chemotherapy ; Deoxycytidine - analogs & derivatives ; Deoxycytidine - pharmacology ; Female ; Gemcitabine ; Genetic aspects ; Health aspects ; Human Genetics ; Humans ; Immune system ; Internal Medicine ; Medical prognosis ; Medicine ; Medicine & Public Health ; Mice ; Mice, Inbred BALB C ; Mice, Inbred NOD ; Molecular Targeted Therapy ; Oncology ; Pancreas ; Pancreatic cancer ; Pancreatic Neoplasms - drug therapy ; Pancreatic Neoplasms - metabolism ; Pancreatic Neoplasms - pathology ; Pancreatic tumors ; Patient outcomes ; Patients ; Precision medicine ; Prognosis ; Survival ; Survival Analysis ; Therapeutic targets ; TLR2 ; TLR2 protein ; Toll-Like Receptor 2 - antagonists & inhibitors ; Toll-Like Receptor 2 - metabolism ; Toll-like receptors ; Transcriptomes ; Tumors ; Xenograft Model Antitumor Assays ; Xenografts</subject><ispartof>Oncogene, 2021-10, Vol.40 (41), p.6007-6022</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2021</rights><rights>2021. The Author(s), under exclusive licence to Springer Nature Limited.</rights><rights>COPYRIGHT 2021 Nature Publishing Group</rights><rights>The Author(s), under exclusive licence to Springer Nature Limited 2021.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c442t-9181f8d45d4f3d725cfa625ed365c8b2dcfab807e4df1c018b0d102251bc2c7a3</citedby><cites>FETCH-LOGICAL-c442t-9181f8d45d4f3d725cfa625ed365c8b2dcfab807e4df1c018b0d102251bc2c7a3</cites><orcidid>0000-0002-7552-4656 ; 0000-0003-3508-3056</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34400766$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lundy, Joanne</creatorcontrib><creatorcontrib>Gearing, Linden J.</creatorcontrib><creatorcontrib>Gao, Hugh</creatorcontrib><creatorcontrib>West, Alison C.</creatorcontrib><creatorcontrib>McLeod, Louise</creatorcontrib><creatorcontrib>Deswaerte, Virginie</creatorcontrib><creatorcontrib>Yu, Liang</creatorcontrib><creatorcontrib>Porazinski, Sean</creatorcontrib><creatorcontrib>Pajic, Marina</creatorcontrib><creatorcontrib>Hertzog, Paul J.</creatorcontrib><creatorcontrib>Croagh, Daniel</creatorcontrib><creatorcontrib>Jenkins, Brendan J.</creatorcontrib><title>TLR2 activation promotes tumour growth and associates with patient survival and chemotherapy response in pancreatic ductal adenocarcinoma</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis, and is plagued by a paucity of targeted treatment options and tumour resistance to chemotherapeutics. The causal link between chronic inflammation and PDAC suggests that molecular regulators of the immune system promote disease pathogenesis and/or therapeutic resistance, yet their identity is unclear. Here, we couple endoscopic ultrasound-guided fine-needle aspiration, which captures tumour biopsies from all stages, with whole transcriptome profiling of PDAC patient primary tumours to reveal enrichment of the innate immune Toll-like receptor 2 (TLR2) molecular pathway. Augmented TLR2 expression associated with a 4-gene “TLR2 activation” signature, and was prognostic for survival and predictive for gemcitabine-based chemoresistance. Furthermore, antibody-mediated anti-TLR2 therapy suppressed the growth of human PDAC tumour xenografts, independent of a functional immune system. 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The causal link between chronic inflammation and PDAC suggests that molecular regulators of the immune system promote disease pathogenesis and/or therapeutic resistance, yet their identity is unclear. Here, we couple endoscopic ultrasound-guided fine-needle aspiration, which captures tumour biopsies from all stages, with whole transcriptome profiling of PDAC patient primary tumours to reveal enrichment of the innate immune Toll-like receptor 2 (TLR2) molecular pathway. Augmented TLR2 expression associated with a 4-gene “TLR2 activation” signature, and was prognostic for survival and predictive for gemcitabine-based chemoresistance. Furthermore, antibody-mediated anti-TLR2 therapy suppressed the growth of human PDAC tumour xenografts, independent of a functional immune system. Our results support TLR2-based therapeutic targeting for precision medicine in PDAC, with further clinical utility that TLR2 activation is prognostic and predictive for chemoresponsiveness.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>34400766</pmid><doi>10.1038/s41388-021-01992-2</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0002-7552-4656</orcidid><orcidid>https://orcid.org/0000-0003-3508-3056</orcidid></addata></record> |
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| subjects | 38/1 38/23 38/39 38/77 38/91 45 631/250/262 631/67/1059/2326 631/67/1059/602 631/67/1504/1713 64/60 82/51 Adenocarcinoma Animals Apoptosis Biopsy Cancer Carcinoma, Pancreatic Ductal - drug therapy Carcinoma, Pancreatic Ductal - metabolism Carcinoma, Pancreatic Ductal - pathology Care and treatment Cell Biology Cell Growth Processes - drug effects Cell Growth Processes - physiology Cell Line, Tumor Cellular signal transduction Chemoresistance Chemotherapy Deoxycytidine - analogs & derivatives Deoxycytidine - pharmacology Female Gemcitabine Genetic aspects Health aspects Human Genetics Humans Immune system Internal Medicine Medical prognosis Medicine Medicine & Public Health Mice Mice, Inbred BALB C Mice, Inbred NOD Molecular Targeted Therapy Oncology Pancreas Pancreatic cancer Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - pathology Pancreatic tumors Patient outcomes Patients Precision medicine Prognosis Survival Survival Analysis Therapeutic targets TLR2 TLR2 protein Toll-Like Receptor 2 - antagonists & inhibitors Toll-Like Receptor 2 - metabolism Toll-like receptors Transcriptomes Tumors Xenograft Model Antitumor Assays Xenografts |
| title | TLR2 activation promotes tumour growth and associates with patient survival and chemotherapy response in pancreatic ductal adenocarcinoma |
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