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https://hdl.handle.net/2440/140038
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Type: | Journal article |
Title: | TLR2 activation promotes tumour growth and associates with patient survival and chemotherapy response in pancreatic ductal adenocarcinoma |
Author: | Lundy, J. Gearing, L.J. Gao, H. West, A.C. McLeod, L. Deswaerte, V. Yu, L. Porazinski, S. Pajic, M. Hertzog, P.J. Croagh, D. Jenkins, B.J. |
Citation: | Oncogene, 2021; 40(41):6007-6022 |
Publisher: | Springer Science and Business Media LLC |
Issue Date: | 2021 |
ISSN: | 0950-9232 1476-5594 |
Statement of Responsibility: | Joanne Lundy, Linden J. Gearing, Hugh Gao, Alison C. West, Louise McLeod, Virginie Deswaerte, Liang Yu, Sean Porazinski, Marina Pajic, Paul J. Hertzog, Daniel Croagh, and Brendan J. Jenkins |
Abstract: | 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. |
Keywords: | Cell Line, Tumor Animals Mice, Inbred BALB C Mice, Inbred NOD Humans Mice Carcinoma, Pancreatic Ductal Pancreatic Neoplasms Deoxycytidine Prognosis Survival Analysis Xenograft Model Antitumor Assays Cell Growth Processes Female Toll-Like Receptor 2 Molecular Targeted Therapy Gemcitabine Cancer therapeutic resistance; Innate immunity; Pancreatic cancer; Targeted therapies |
Rights: | © 2021, The Author(s), under exclusive licence to Springer Nature Limited |
DOI: | 10.1038/s41388-021-01992-2 |
Published version: | http://dx.doi.org/10.1038/s41388-021-01992-2 |
Appears in Collections: | Medicine publications |
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