A new pancreatic adenocarcinoma‐derived organoid model of acquired chemoresistance to FOLFIRINOX: first insight of the underlying mechanisms
| العنوان: | A new pancreatic adenocarcinoma‐derived organoid model of acquired chemoresistance to FOLFIRINOX: first insight of the underlying mechanisms |
|---|---|
| المؤلفون: | Nicolas Stoup, Chann Lagadec, Antonino Bongiovanni, Marie Vandepeutte, Audrey Vincent, Belinda Duchêne, Laurent Poulain, Sonia Paget, Emmanuelle Leteurtre, Nathalie Jouy, Florence Renaud, Fabienne Escande, Louis-Bastien Weiswald, Soumaya El Moghrabi, Charles Poiraud, Elsa Hadj Bachir, Nicolas Jonckheere, Stéphanie Truant, César Beugniez, Meryem Tardivel, Pascal Pigny, Isabelle Van Seuningen |
| المساهمون: | Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), CHU Lille, Plateformes Lilloises en Biologie et Santé - UAR 2014 - US 41 (PLBS), Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), VINCENT, AUDREY, Plateformes Lilloises en Biologie et Santé - UMS 2014 - US 41 (PLBS), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER, UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU) |
| المصدر: | Biology of the Cell Biology of the Cell, Wiley, 2021, ⟨10.1111/boc.202100003⟩ Biology of the Cell, In press, ⟨10.1111/boc.202100003⟩ Biology of the Cell, Wiley, In press, ⟨10.1111/boc.202100003⟩ |
| بيانات النشر: | HAL CCSD, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Oncology, medicine.medical_specialty, FOLFIRINOX, [SDV]Life Sciences [q-bio], Leucovorin, [SDV.CAN]Life Sciences [q-bio]/Cancer, Adenocarcinoma, Biology, Irinotecan, 03 medical and health sciences, 0302 clinical medicine, Cell quiescence, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Pancreatic cancer, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Cancer, Cell Biology, General Medicine, medicine.disease, 3. Good health, Oxaliplatin, Organoids, Pancreatic Neoplasms, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Fluorouracil, Folfirinox Regimen, medicine.drug |
| الوصف: | International audience; Background information: Although improvements have been made in the management of pancreatic adenocarcinoma (PDAC) during the past 20 years, the prognosis of this deadly disease remains poor with an overall 5-year survival under 10%. Treatment with FOLFIRINOX, a combined regimen of 5-fluorouracil, irinotecan (SN-38) and oxaliplatin, is nonetheless associated with an excellent initial tumor response and its use has allowed numerous patients to go through surgery while their tumor was initially considered unresectable. These discrepancies between initial tumor response and very low long-term survival are the consequences of rapidly acquired chemoresistance and represent a major therapeutic frontier. To our knowledge, a model of resistance to the combined three drugs has never been described due to the difficulty of modeling the FOLFIRINOX protocol both in vitro and in vivo. Patient-Derived tumour Organoids (PDO) are the missing link that has long been lacking in the wide range of epithelial cancer models between 2D adherent cultures and in vivo xenografts. In this work we sought to set up a model of PDO with resistance to FOLFIRINOX regimen that we could compare to the paired naive PDO.Results: We first extrapolated physiological concentrations of the three drugs using previous pharmacodynamics studies and bi-compartmental elimination models of oxaliplatin and SN-38. We then treated PaTa-1818x naive PDAC organoids with six cycles of 72h- FOLFIRINOX treatment followed by 96h interruption. Thereafter, we systematically compared treated organoids to PaTa-1818x naive organoids in terms of growth, proliferation, viability and expression of genes involved in cancer stemness and aggressiveness.Conclusions: We reproductively obtained resistant organoids FoxR that significantly showed less sensitivity to FOLFORINOX treatment than the PaTa-1818x naive organoids from which they were derived. Our resistant model is representative of the sequential steps of chemoresistance observed in patients in terms of growth arrest (proliferation blockade), residual disease (cell quiescence/dormancy) and relapse.Significance: To our knowledge, this is the first genuine in vitro model of resistance to the three drugs in combined therapy. This new PDO model will be a great asset for the discovery of acquired chemoresistance mechanisms, knowledge that is mandatory before offering new therapeutic strategies for pancreatic cancer. This article is protected by copyright. All rights reserved. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 0248-4900 1768-322X |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2e1ec8ef20d432bc1ca36367bd2a99dfTest https://hal.archives-ouvertes.fr/hal-03379163Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....2e1ec8ef20d432bc1ca36367bd2a99df |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 02484900 1768322X |
|---|