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Talniflumate abrogates mucin immune suppressive barrier improving efficacy of gemcitabine and nab-paclitaxel treatment in pancreatic cancer
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. This is due to its aggressive course, late diagnosis and its intrinsic drugs resistance. The complexity of the tumor, in terms of cell components and heterogeneity, has led to the approval of few therapies with limited efficacy...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10668479/ https://www.ncbi.nlm.nih.gov/pubmed/37996891 http://dx.doi.org/10.1186/s12967-023-04733-z |
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author | Agostini, Antonio Guerriero, Ilaria Piro, Geny Quero, Giuseppe Roberto, Luca Esposito, Annachiara Caggiano, Alessia Priori, Lorenzo Scaglione, Giulia De Sanctis, Francesco Sistigu, Antonella Musella, Martina Larghi, Alberto Rizzatti, Gianenrico Lucchetti, Donatella Alfieri, Sergio Sgambato, Alessandro Bria, Emilio Bizzozero, Laura Arena, Sabrina Ugel, Stefano Corbo, Vincenzo Tortora, Giampaolo Carbone, Carmine |
author_facet | Agostini, Antonio Guerriero, Ilaria Piro, Geny Quero, Giuseppe Roberto, Luca Esposito, Annachiara Caggiano, Alessia Priori, Lorenzo Scaglione, Giulia De Sanctis, Francesco Sistigu, Antonella Musella, Martina Larghi, Alberto Rizzatti, Gianenrico Lucchetti, Donatella Alfieri, Sergio Sgambato, Alessandro Bria, Emilio Bizzozero, Laura Arena, Sabrina Ugel, Stefano Corbo, Vincenzo Tortora, Giampaolo Carbone, Carmine |
author_sort | Agostini, Antonio |
collection | PubMed |
description | BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. This is due to its aggressive course, late diagnosis and its intrinsic drugs resistance. The complexity of the tumor, in terms of cell components and heterogeneity, has led to the approval of few therapies with limited efficacy. The study of the early stages of carcinogenesis provides the opportunity for the identification of actionable pathways that underpin therapeutic resistance. METHODS: We analyzed 43 Intraductal papillary mucinous neoplasms (IPMN) (12 Low-grade and 31 High-grade) by Spatial Transcriptomics. Mouse and human pancreatic cancer organoids and T cells interaction platforms were established to test the role of mucins expression on T cells activity. Syngeneic mouse model of PDAC was used to explore the impact of mucins downregulation on standard therapy efficacy. RESULTS: Spatial transcriptomics showed that mucin O-glycosylation pathway is increased in the progression from low-grade to high-grade IPMN. We identified GCNT3, a master regulator of mucins expression, as an actionable target of this pathway by talniflumate. We showed that talniflumate impaired mucins expression increasing T cell activation and recognition using both mouse and human organoid interaction platforms. In vivo experiments showed that talniflumate was able to increase the efficacy of the chemotherapy by boosting immune infiltration. CONCLUSIONS: Finally, we demonstrated that combination of talniflumate, an anti-inflammatory drug, with chemotherapy effectively improves anti-tumor effect in PDAC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-023-04733-z. |
format | Online Article Text |
id | pubmed-10668479 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-106684792023-11-23 Talniflumate abrogates mucin immune suppressive barrier improving efficacy of gemcitabine and nab-paclitaxel treatment in pancreatic cancer Agostini, Antonio Guerriero, Ilaria Piro, Geny Quero, Giuseppe Roberto, Luca Esposito, Annachiara Caggiano, Alessia Priori, Lorenzo Scaglione, Giulia De Sanctis, Francesco Sistigu, Antonella Musella, Martina Larghi, Alberto Rizzatti, Gianenrico Lucchetti, Donatella Alfieri, Sergio Sgambato, Alessandro Bria, Emilio Bizzozero, Laura Arena, Sabrina Ugel, Stefano Corbo, Vincenzo Tortora, Giampaolo Carbone, Carmine J Transl Med Research BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. This is due to its aggressive course, late diagnosis and its intrinsic drugs resistance. The complexity of the tumor, in terms of cell components and heterogeneity, has led to the approval of few therapies with limited efficacy. The study of the early stages of carcinogenesis provides the opportunity for the identification of actionable pathways that underpin therapeutic resistance. METHODS: We analyzed 43 Intraductal papillary mucinous neoplasms (IPMN) (12 Low-grade and 31 High-grade) by Spatial Transcriptomics. Mouse and human pancreatic cancer organoids and T cells interaction platforms were established to test the role of mucins expression on T cells activity. Syngeneic mouse model of PDAC was used to explore the impact of mucins downregulation on standard therapy efficacy. RESULTS: Spatial transcriptomics showed that mucin O-glycosylation pathway is increased in the progression from low-grade to high-grade IPMN. We identified GCNT3, a master regulator of mucins expression, as an actionable target of this pathway by talniflumate. We showed that talniflumate impaired mucins expression increasing T cell activation and recognition using both mouse and human organoid interaction platforms. In vivo experiments showed that talniflumate was able to increase the efficacy of the chemotherapy by boosting immune infiltration. CONCLUSIONS: Finally, we demonstrated that combination of talniflumate, an anti-inflammatory drug, with chemotherapy effectively improves anti-tumor effect in PDAC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-023-04733-z. BioMed Central 2023-11-23 /pmc/articles/PMC10668479/ /pubmed/37996891 http://dx.doi.org/10.1186/s12967-023-04733-z Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Agostini, Antonio Guerriero, Ilaria Piro, Geny Quero, Giuseppe Roberto, Luca Esposito, Annachiara Caggiano, Alessia Priori, Lorenzo Scaglione, Giulia De Sanctis, Francesco Sistigu, Antonella Musella, Martina Larghi, Alberto Rizzatti, Gianenrico Lucchetti, Donatella Alfieri, Sergio Sgambato, Alessandro Bria, Emilio Bizzozero, Laura Arena, Sabrina Ugel, Stefano Corbo, Vincenzo Tortora, Giampaolo Carbone, Carmine Talniflumate abrogates mucin immune suppressive barrier improving efficacy of gemcitabine and nab-paclitaxel treatment in pancreatic cancer |
title | Talniflumate abrogates mucin immune suppressive barrier improving efficacy of gemcitabine and nab-paclitaxel treatment in pancreatic cancer |
title_full | Talniflumate abrogates mucin immune suppressive barrier improving efficacy of gemcitabine and nab-paclitaxel treatment in pancreatic cancer |
title_fullStr | Talniflumate abrogates mucin immune suppressive barrier improving efficacy of gemcitabine and nab-paclitaxel treatment in pancreatic cancer |
title_full_unstemmed | Talniflumate abrogates mucin immune suppressive barrier improving efficacy of gemcitabine and nab-paclitaxel treatment in pancreatic cancer |
title_short | Talniflumate abrogates mucin immune suppressive barrier improving efficacy of gemcitabine and nab-paclitaxel treatment in pancreatic cancer |
title_sort | talniflumate abrogates mucin immune suppressive barrier improving efficacy of gemcitabine and nab-paclitaxel treatment in pancreatic cancer |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10668479/ https://www.ncbi.nlm.nih.gov/pubmed/37996891 http://dx.doi.org/10.1186/s12967-023-04733-z |
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