Extracellular matrix collagen I differentially regulates the metabolic plasticity of pancreatic ductal adenocarcinoma parenchymal cell and cancer stem cell
Autor(a) principal: | |
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Data de Publicação: | 2023 |
Outros Autores: | , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | https://hdl.handle.net/1822/87060 |
Resumo: | Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of less than 10 percent largely due to the intense fibrotic desmoplastic reaction, characterized by high levels of extracellular matrix (ECM) collagen I that constitutes a niche for a subset of cancer cells, the cancer stem cells (CSCs). Cancer cells undergo a complex metabolic adaptation characterized by changes in metabolic pathways and biosynthetic processes. The use of the 3D organotypic model in this study allowed us to manipulate the ECM constituents and mimic the progression of PDAC from an early tumor to an ever more advanced tumor stage. To understand the role of desmoplasia on the metabolism of PDAC parenchymal (CPC) and CSC populations, we studied their basic metabolic parameters in organotypic cultures of increasing collagen content to mimic in vivo conditions. We further measured the ability of the bioenergetic modulators (BMs), 2-deoxyglucose, dichloroacetate and phenformin, to modify their metabolic dependence and the therapeutic activity of paclitaxel albumin nanoparticles (NAB-PTX). While all the BMs decreased cell viability and increased cell death in all ECM types, a distinct, collagen I-dependent profile was observed in CSCs. As ECM collagen I content increased (e.g., more aggressive conditions), the CSCs switched from glucose to mostly glutamine metabolism. All three BMs synergistically potentiated the cytotoxicity of NAB-PTX in both cell lines, which, in CSCs, was collagen I-dependent and the strongest when treated with phenformin + NAB-PTX. Metabolic disruption in PDAC can be useful both as monotherapy or combined with conventional drugs to more efficiently block tumor growth. |
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Extracellular matrix collagen I differentially regulates the metabolic plasticity of pancreatic ductal adenocarcinoma parenchymal cell and cancer stem cellPancreatic ductal adenocarcinomaTumor microenvironmentChemoresistanceTreatmentCancer stem cellsCollagen IBioenergetic modulatorsGlutaminePancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of less than 10 percent largely due to the intense fibrotic desmoplastic reaction, characterized by high levels of extracellular matrix (ECM) collagen I that constitutes a niche for a subset of cancer cells, the cancer stem cells (CSCs). Cancer cells undergo a complex metabolic adaptation characterized by changes in metabolic pathways and biosynthetic processes. The use of the 3D organotypic model in this study allowed us to manipulate the ECM constituents and mimic the progression of PDAC from an early tumor to an ever more advanced tumor stage. To understand the role of desmoplasia on the metabolism of PDAC parenchymal (CPC) and CSC populations, we studied their basic metabolic parameters in organotypic cultures of increasing collagen content to mimic in vivo conditions. We further measured the ability of the bioenergetic modulators (BMs), 2-deoxyglucose, dichloroacetate and phenformin, to modify their metabolic dependence and the therapeutic activity of paclitaxel albumin nanoparticles (NAB-PTX). While all the BMs decreased cell viability and increased cell death in all ECM types, a distinct, collagen I-dependent profile was observed in CSCs. As ECM collagen I content increased (e.g., more aggressive conditions), the CSCs switched from glucose to mostly glutamine metabolism. All three BMs synergistically potentiated the cytotoxicity of NAB-PTX in both cell lines, which, in CSCs, was collagen I-dependent and the strongest when treated with phenformin + NAB-PTX. Metabolic disruption in PDAC can be useful both as monotherapy or combined with conventional drugs to more efficiently block tumor growth.This work has been funded by National funds, through the Foundation for Science and Technology (FCT)—project UIDB/50026/2020 and UIDP/50026/2020; and by the project NORTE-01- 0145-FEDER-000055, supported by Norte Portugal Regional Operational Program (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). DT-V received a fellowship from FCT (ref. SFRH/BD/103025/2014). T.A.M.C. was funded by the European Marie Skłodowska-Curie Innovative Training Network (ITN) pH and Ion Transport in Pancreatic Cancer–pHioniC (grant agreement number: 813834; H2020-MSCA-ITN-2018).Multidisciplinary Digital Publishing Institute (MDPI)Universidade do MinhoTavares-Valente, DianaCannone, StefaniaGreco, Maria RaffaellaCarvalho, Tiago Miguel AmaralBaltazar, FátimaQueirós, OdíliaAgrimi, GennaroReshkin, Stephan J.Cardone, Rosa Angela2023-07-292023-07-29T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/1822/87060engTavares-Valente, D.; Cannone, S.; Greco, M.R.; Carvalho, T.M.A.; Baltazar, F.; Queirós, O.; Agrimi, G.; Reshkin, S.J.; Cardone, R.A. Extracellular Matrix Collagen I Differentially Regulates the Metabolic Plasticity of Pancreatic Ductal Adenocarcinoma Parenchymal Cell and Cancer Stem Cell. Cancers 2023, 15, 3868. https://doi.org/10.3390/cancers151538682072-669410.3390/cancers151538683868https://www.mdpi.com/2072-6694/15/15/3868info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-10-28T01:19:41Zoai:repositorium.sdum.uminho.pt:1822/87060Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:26:00.348463Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Extracellular matrix collagen I differentially regulates the metabolic plasticity of pancreatic ductal adenocarcinoma parenchymal cell and cancer stem cell |
title |
Extracellular matrix collagen I differentially regulates the metabolic plasticity of pancreatic ductal adenocarcinoma parenchymal cell and cancer stem cell |
spellingShingle |
Extracellular matrix collagen I differentially regulates the metabolic plasticity of pancreatic ductal adenocarcinoma parenchymal cell and cancer stem cell Tavares-Valente, Diana Pancreatic ductal adenocarcinoma Tumor microenvironment Chemoresistance Treatment Cancer stem cells Collagen I Bioenergetic modulators Glutamine |
title_short |
Extracellular matrix collagen I differentially regulates the metabolic plasticity of pancreatic ductal adenocarcinoma parenchymal cell and cancer stem cell |
title_full |
Extracellular matrix collagen I differentially regulates the metabolic plasticity of pancreatic ductal adenocarcinoma parenchymal cell and cancer stem cell |
title_fullStr |
Extracellular matrix collagen I differentially regulates the metabolic plasticity of pancreatic ductal adenocarcinoma parenchymal cell and cancer stem cell |
title_full_unstemmed |
Extracellular matrix collagen I differentially regulates the metabolic plasticity of pancreatic ductal adenocarcinoma parenchymal cell and cancer stem cell |
title_sort |
Extracellular matrix collagen I differentially regulates the metabolic plasticity of pancreatic ductal adenocarcinoma parenchymal cell and cancer stem cell |
author |
Tavares-Valente, Diana |
author_facet |
Tavares-Valente, Diana Cannone, Stefania Greco, Maria Raffaella Carvalho, Tiago Miguel Amaral Baltazar, Fátima Queirós, Odília Agrimi, Gennaro Reshkin, Stephan J. Cardone, Rosa Angela |
author_role |
author |
author2 |
Cannone, Stefania Greco, Maria Raffaella Carvalho, Tiago Miguel Amaral Baltazar, Fátima Queirós, Odília Agrimi, Gennaro Reshkin, Stephan J. Cardone, Rosa Angela |
author2_role |
author author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade do Minho |
dc.contributor.author.fl_str_mv |
Tavares-Valente, Diana Cannone, Stefania Greco, Maria Raffaella Carvalho, Tiago Miguel Amaral Baltazar, Fátima Queirós, Odília Agrimi, Gennaro Reshkin, Stephan J. Cardone, Rosa Angela |
dc.subject.por.fl_str_mv |
Pancreatic ductal adenocarcinoma Tumor microenvironment Chemoresistance Treatment Cancer stem cells Collagen I Bioenergetic modulators Glutamine |
topic |
Pancreatic ductal adenocarcinoma Tumor microenvironment Chemoresistance Treatment Cancer stem cells Collagen I Bioenergetic modulators Glutamine |
description |
Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of less than 10 percent largely due to the intense fibrotic desmoplastic reaction, characterized by high levels of extracellular matrix (ECM) collagen I that constitutes a niche for a subset of cancer cells, the cancer stem cells (CSCs). Cancer cells undergo a complex metabolic adaptation characterized by changes in metabolic pathways and biosynthetic processes. The use of the 3D organotypic model in this study allowed us to manipulate the ECM constituents and mimic the progression of PDAC from an early tumor to an ever more advanced tumor stage. To understand the role of desmoplasia on the metabolism of PDAC parenchymal (CPC) and CSC populations, we studied their basic metabolic parameters in organotypic cultures of increasing collagen content to mimic in vivo conditions. We further measured the ability of the bioenergetic modulators (BMs), 2-deoxyglucose, dichloroacetate and phenformin, to modify their metabolic dependence and the therapeutic activity of paclitaxel albumin nanoparticles (NAB-PTX). While all the BMs decreased cell viability and increased cell death in all ECM types, a distinct, collagen I-dependent profile was observed in CSCs. As ECM collagen I content increased (e.g., more aggressive conditions), the CSCs switched from glucose to mostly glutamine metabolism. All three BMs synergistically potentiated the cytotoxicity of NAB-PTX in both cell lines, which, in CSCs, was collagen I-dependent and the strongest when treated with phenformin + NAB-PTX. Metabolic disruption in PDAC can be useful both as monotherapy or combined with conventional drugs to more efficiently block tumor growth. |
publishDate |
2023 |
dc.date.none.fl_str_mv |
2023-07-29 2023-07-29T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
https://hdl.handle.net/1822/87060 |
url |
https://hdl.handle.net/1822/87060 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Tavares-Valente, D.; Cannone, S.; Greco, M.R.; Carvalho, T.M.A.; Baltazar, F.; Queirós, O.; Agrimi, G.; Reshkin, S.J.; Cardone, R.A. Extracellular Matrix Collagen I Differentially Regulates the Metabolic Plasticity of Pancreatic Ductal Adenocarcinoma Parenchymal Cell and Cancer Stem Cell. Cancers 2023, 15, 3868. https://doi.org/10.3390/cancers15153868 2072-6694 10.3390/cancers15153868 3868 https://www.mdpi.com/2072-6694/15/15/3868 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Multidisciplinary Digital Publishing Institute (MDPI) |
publisher.none.fl_str_mv |
Multidisciplinary Digital Publishing Institute (MDPI) |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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