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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Vydáno v:	Oncogene Ročník 40; číslo 41; s. 6007 - 6022
Hlavní autoři:	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.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 14.10.2021 Nature Publishing Group
Témata:	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 Australia
ISSN:	0950-9232, 1476-5594, 1476-5594
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0950-9232 1476-5594 1476-5594
DOI:	10.1038/s41388-021-01992-2