TLR2 activation promotes tumour growth and associates with patient survival and chemotherapy response in pancreatic ductal adenocarcinoma.
Animals
Carcinoma, Pancreatic Ductal
/ drug therapy
Cell Growth Processes
/ drug effects
Cell Line, Tumor
Deoxycytidine
/ analogs & derivatives
Female
Humans
Mice
Mice, Inbred BALB C
Mice, Inbred NOD
Molecular Targeted Therapy
Pancreatic Neoplasms
/ drug therapy
Prognosis
Survival Analysis
Toll-Like Receptor 2
/ antagonists & inhibitors
Xenograft Model Antitumor Assays
Gemcitabine
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
received:
02
09
2020
accepted:
06
08
2021
revised:
05
08
2021
pubmed:
18
8
2021
medline:
27
1
2022
entrez:
17
8
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34400766
doi: 10.1038/s41388-021-01992-2
pii: 10.1038/s41388-021-01992-2
doi:
Substances chimiques
TLR2 protein, human
0
Toll-Like Receptor 2
0
Deoxycytidine
0W860991D6
Gemcitabine
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6007-6022Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature Limited.
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