Evidencing a pancreatic ductal adenocarcinoma subpopulation sensitive to the proteasome inhibitor Carfilzomib

Autores
Fraunhoffer Navarro, Nicolas Alejandro; Meilerman Abuelafia, Miriam Analia; Bigonnet, Martin; Gayet, Odile; Roque, Julie; Telle, Emmanuel; Santofimia-Castaño, Patricia; Borrello, Maria Teresa; Chuluyan, Hector Eduardo; Dusetti, Nelson; Iovanna, Juan Lucio
Año de publicación
2020
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a survival rate less than 5%. Multiple chemotherapeutic drugs have been tested to improve patient prognosis; however, the clinical efficacy of these treatments is low. One of the most controversial family of drugs are the proteasome inhibitors, which have displayed promising effects in preclinical studies, but low clinical performance. Here, we unravel a specific transcriptomic signature that discriminates a subgroup of patients sensitive to the proteasome inhibitor carfilzomib. Experimental Design: First, we identified a subpopulation of PDAC-derived primary cells cultures (PDPCC) sensitive to the proteasome inhibitor carfilzomib. Then, we selected a transcriptomic signature that predicts carfilzomib chemosensitivity using independent component analysis on the transcriptome of PDPCC. Finally, we validated the signature in an independent cohort of PDAC biopsy-derived pancreatic organoids. Results: Sensitive phenotype was characterized by a high expression of genes related with a cornified/squamous pathway and a downregulation of epithelial-mesenchymal transition genes. Interestingly, carfilzomib-sensitive transcriptomic profile did not show any association with the proteasome activity but strongly correlates with ATF4 and CHOP expression, which are key markers of the unfolded protein response and critical to trigger the cell death program. Concordantly, sensitive phenotype showed a high level of the de novo RNA and protein synthesis compared with the resistant one and, most important, cell death induced by carfilzomib is dependent of the translational activity. Conclusions: We demonstrate the existence of a carfilzomib-sensitive PDAC subgroup with a specific transcriptomic phenotype that could explain the biological reason for this responsiveness.
Fil: Fraunhoffer Navarro, Nicolas Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina. Inserm; Francia
Fil: Meilerman Abuelafia, Miriam Analia. Inserm; Francia
Fil: Bigonnet, Martin. Inserm; Francia
Fil: Gayet, Odile. Inserm; Francia
Fil: Roque, Julie. Inserm; Francia
Fil: Telle, Emmanuel. Inserm; Francia
Fil: Santofimia-Castaño, Patricia. Inserm; Francia
Fil: Borrello, Maria Teresa. Inserm; Francia
Fil: Chuluyan, Hector Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina
Fil: Dusetti, Nelson. Inserm; Francia
Fil: Iovanna, Juan Lucio. Inserm; Francia
Materia
CANCER
PANCREAS
PROTEOSOMA
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/132501
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/132501
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Evidencing a pancreatic ductal adenocarcinoma subpopulation sensitive to the proteasome inhibitor CarfilzomibFraunhoffer Navarro, Nicolas AlejandroMeilerman Abuelafia, Miriam AnaliaBigonnet, MartinGayet, OdileRoque, JulieTelle, EmmanuelSantofimia-Castaño, PatriciaBorrello, Maria TeresaChuluyan, Hector EduardoDusetti, NelsonIovanna, Juan LucioCANCERPANCREASPROTEOSOMAhttps://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a survival rate less than 5%. Multiple chemotherapeutic drugs have been tested to improve patient prognosis; however, the clinical efficacy of these treatments is low. One of the most controversial family of drugs are the proteasome inhibitors, which have displayed promising effects in preclinical studies, but low clinical performance. Here, we unravel a specific transcriptomic signature that discriminates a subgroup of patients sensitive to the proteasome inhibitor carfilzomib. Experimental Design: First, we identified a subpopulation of PDAC-derived primary cells cultures (PDPCC) sensitive to the proteasome inhibitor carfilzomib. Then, we selected a transcriptomic signature that predicts carfilzomib chemosensitivity using independent component analysis on the transcriptome of PDPCC. Finally, we validated the signature in an independent cohort of PDAC biopsy-derived pancreatic organoids. Results: Sensitive phenotype was characterized by a high expression of genes related with a cornified/squamous pathway and a downregulation of epithelial-mesenchymal transition genes. Interestingly, carfilzomib-sensitive transcriptomic profile did not show any association with the proteasome activity but strongly correlates with ATF4 and CHOP expression, which are key markers of the unfolded protein response and critical to trigger the cell death program. Concordantly, sensitive phenotype showed a high level of the de novo RNA and protein synthesis compared with the resistant one and, most important, cell death induced by carfilzomib is dependent of the translational activity. Conclusions: We demonstrate the existence of a carfilzomib-sensitive PDAC subgroup with a specific transcriptomic phenotype that could explain the biological reason for this responsiveness.Fil: Fraunhoffer Navarro, Nicolas Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina. Inserm; FranciaFil: Meilerman Abuelafia, Miriam Analia. Inserm; FranciaFil: Bigonnet, Martin. Inserm; FranciaFil: Gayet, Odile. Inserm; FranciaFil: Roque, Julie. Inserm; FranciaFil: Telle, Emmanuel. Inserm; FranciaFil: Santofimia-Castaño, Patricia. Inserm; FranciaFil: Borrello, Maria Teresa. Inserm; FranciaFil: Chuluyan, Hector Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Dusetti, Nelson. Inserm; FranciaFil: Iovanna, Juan Lucio. Inserm; FranciaAmerican Association for Cancer Research2020-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/132501Fraunhoffer Navarro, Nicolas Alejandro; Meilerman Abuelafia, Miriam Analia; Bigonnet, Martin; Gayet, Odile; Roque, Julie; et al.; Evidencing a pancreatic ductal adenocarcinoma subpopulation sensitive to the proteasome inhibitor Carfilzomib; American Association for Cancer Research; Clinical Cancer Research; 26; 20; 10-2020; 5506-55191078-0432CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://clincancerres.aacrjournals.org/lookup/doi/10.1158/1078-0432.CCR-20-1232info:eu-repo/semantics/altIdentifier/doi/10.1158/1078-0432.CCR-20-1232info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-10T13:00:27Zoai:ri.conicet.gov.ar:11336/132501instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-10 13:00:28.201CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Evidencing a pancreatic ductal adenocarcinoma subpopulation sensitive to the proteasome inhibitor Carfilzomib
title Evidencing a pancreatic ductal adenocarcinoma subpopulation sensitive to the proteasome inhibitor Carfilzomib
spellingShingle Evidencing a pancreatic ductal adenocarcinoma subpopulation sensitive to the proteasome inhibitor Carfilzomib
Fraunhoffer Navarro, Nicolas Alejandro
CANCER
PANCREAS
PROTEOSOMA
title_short Evidencing a pancreatic ductal adenocarcinoma subpopulation sensitive to the proteasome inhibitor Carfilzomib
title_full Evidencing a pancreatic ductal adenocarcinoma subpopulation sensitive to the proteasome inhibitor Carfilzomib
title_fullStr Evidencing a pancreatic ductal adenocarcinoma subpopulation sensitive to the proteasome inhibitor Carfilzomib
title_full_unstemmed Evidencing a pancreatic ductal adenocarcinoma subpopulation sensitive to the proteasome inhibitor Carfilzomib
title_sort Evidencing a pancreatic ductal adenocarcinoma subpopulation sensitive to the proteasome inhibitor Carfilzomib
dc.creator.none.fl_str_mv Fraunhoffer Navarro, Nicolas Alejandro
Meilerman Abuelafia, Miriam Analia
Bigonnet, Martin
Gayet, Odile
Roque, Julie
Telle, Emmanuel
Santofimia-Castaño, Patricia
Borrello, Maria Teresa
Chuluyan, Hector Eduardo
Dusetti, Nelson
Iovanna, Juan Lucio
author Fraunhoffer Navarro, Nicolas Alejandro
author_facet Fraunhoffer Navarro, Nicolas Alejandro
Meilerman Abuelafia, Miriam Analia
Bigonnet, Martin
Gayet, Odile
Roque, Julie
Telle, Emmanuel
Santofimia-Castaño, Patricia
Borrello, Maria Teresa
Chuluyan, Hector Eduardo
Dusetti, Nelson
Iovanna, Juan Lucio
author_role author
author2 Meilerman Abuelafia, Miriam Analia
Bigonnet, Martin
Gayet, Odile
Roque, Julie
Telle, Emmanuel
Santofimia-Castaño, Patricia
Borrello, Maria Teresa
Chuluyan, Hector Eduardo
Dusetti, Nelson
Iovanna, Juan Lucio
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv CANCER
PANCREAS
PROTEOSOMA
topic CANCER
PANCREAS
PROTEOSOMA
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a survival rate less than 5%. Multiple chemotherapeutic drugs have been tested to improve patient prognosis; however, the clinical efficacy of these treatments is low. One of the most controversial family of drugs are the proteasome inhibitors, which have displayed promising effects in preclinical studies, but low clinical performance. Here, we unravel a specific transcriptomic signature that discriminates a subgroup of patients sensitive to the proteasome inhibitor carfilzomib. Experimental Design: First, we identified a subpopulation of PDAC-derived primary cells cultures (PDPCC) sensitive to the proteasome inhibitor carfilzomib. Then, we selected a transcriptomic signature that predicts carfilzomib chemosensitivity using independent component analysis on the transcriptome of PDPCC. Finally, we validated the signature in an independent cohort of PDAC biopsy-derived pancreatic organoids. Results: Sensitive phenotype was characterized by a high expression of genes related with a cornified/squamous pathway and a downregulation of epithelial-mesenchymal transition genes. Interestingly, carfilzomib-sensitive transcriptomic profile did not show any association with the proteasome activity but strongly correlates with ATF4 and CHOP expression, which are key markers of the unfolded protein response and critical to trigger the cell death program. Concordantly, sensitive phenotype showed a high level of the de novo RNA and protein synthesis compared with the resistant one and, most important, cell death induced by carfilzomib is dependent of the translational activity. Conclusions: We demonstrate the existence of a carfilzomib-sensitive PDAC subgroup with a specific transcriptomic phenotype that could explain the biological reason for this responsiveness.
Fil: Fraunhoffer Navarro, Nicolas Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina. Inserm; Francia
Fil: Meilerman Abuelafia, Miriam Analia. Inserm; Francia
Fil: Bigonnet, Martin. Inserm; Francia
Fil: Gayet, Odile. Inserm; Francia
Fil: Roque, Julie. Inserm; Francia
Fil: Telle, Emmanuel. Inserm; Francia
Fil: Santofimia-Castaño, Patricia. Inserm; Francia
Fil: Borrello, Maria Teresa. Inserm; Francia
Fil: Chuluyan, Hector Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina
Fil: Dusetti, Nelson. Inserm; Francia
Fil: Iovanna, Juan Lucio. Inserm; Francia
description Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a survival rate less than 5%. Multiple chemotherapeutic drugs have been tested to improve patient prognosis; however, the clinical efficacy of these treatments is low. One of the most controversial family of drugs are the proteasome inhibitors, which have displayed promising effects in preclinical studies, but low clinical performance. Here, we unravel a specific transcriptomic signature that discriminates a subgroup of patients sensitive to the proteasome inhibitor carfilzomib. Experimental Design: First, we identified a subpopulation of PDAC-derived primary cells cultures (PDPCC) sensitive to the proteasome inhibitor carfilzomib. Then, we selected a transcriptomic signature that predicts carfilzomib chemosensitivity using independent component analysis on the transcriptome of PDPCC. Finally, we validated the signature in an independent cohort of PDAC biopsy-derived pancreatic organoids. Results: Sensitive phenotype was characterized by a high expression of genes related with a cornified/squamous pathway and a downregulation of epithelial-mesenchymal transition genes. Interestingly, carfilzomib-sensitive transcriptomic profile did not show any association with the proteasome activity but strongly correlates with ATF4 and CHOP expression, which are key markers of the unfolded protein response and critical to trigger the cell death program. Concordantly, sensitive phenotype showed a high level of the de novo RNA and protein synthesis compared with the resistant one and, most important, cell death induced by carfilzomib is dependent of the translational activity. Conclusions: We demonstrate the existence of a carfilzomib-sensitive PDAC subgroup with a specific transcriptomic phenotype that could explain the biological reason for this responsiveness.
publishDate 2020
dc.date.none.fl_str_mv 2020-10
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/132501
Fraunhoffer Navarro, Nicolas Alejandro; Meilerman Abuelafia, Miriam Analia; Bigonnet, Martin; Gayet, Odile; Roque, Julie; et al.; Evidencing a pancreatic ductal adenocarcinoma subpopulation sensitive to the proteasome inhibitor Carfilzomib; American Association for Cancer Research; Clinical Cancer Research; 26; 20; 10-2020; 5506-5519
1078-0432
CONICET Digital
CONICET
url http://hdl.handle.net/11336/132501
identifier_str_mv Fraunhoffer Navarro, Nicolas Alejandro; Meilerman Abuelafia, Miriam Analia; Bigonnet, Martin; Gayet, Odile; Roque, Julie; et al.; Evidencing a pancreatic ductal adenocarcinoma subpopulation sensitive to the proteasome inhibitor Carfilzomib; American Association for Cancer Research; Clinical Cancer Research; 26; 20; 10-2020; 5506-5519
1078-0432
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://clincancerres.aacrjournals.org/lookup/doi/10.1158/1078-0432.CCR-20-1232
info:eu-repo/semantics/altIdentifier/doi/10.1158/1078-0432.CCR-20-1232
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Association for Cancer Research
publisher.none.fl_str_mv American Association for Cancer Research
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1842979882709024768
score 12.993085

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