Induction of lysosome membrane permeabilization as a therapeutic strategy to target pancreatic cancer stem cells

Despite significant efforts to improve pancreatic ductal adenocarcinoma (PDAC) clinical outcomes, overall survival remains dismal. The poor response to current therapies is partly due to the existence of pancreatic cancer stem cells (PaCSCs), which are efficient drivers of PDAC tumorigenesis, metast...

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Autores: Cash, Timothy P., Alcalá, Sonia, Rico-Ferreira, María Del Rosario, Hernández-Encinas, Elena, García, Jennifer, Albarrán, María Isabel, Valle, Sandra, Muñoz, Javier, Martínez-González, Sonia, Blanco-Aparicio, Carmen, Pastor, Joaquín, Serrano, Manuel, Sainz, Bruno
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Universidad Autónoma de Madrid
Repositorio:Biblos-e Archivo. Repositorio Institucional de la UAM
Idioma:inglés
OAI Identifier:oai:repositorio.uam.es:10486/694718
Acceso en línea:http://hdl.handle.net/10486/694718
https://dx.doi.org/10.3390/cancers12071790
Access Level:acceso abierto
Palabra clave:Cancer stem cells
Compound library
Lysosomal membrane permeabilization
Pancreatic ductal adenocarcinoma
Patient-derived xenografts
Medicina
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spelling Induction of lysosome membrane permeabilization as a therapeutic strategy to target pancreatic cancer stem cellsCash, Timothy P.Alcalá, SoniaRico-Ferreira, María Del RosarioHernández-Encinas, ElenaGarcía, JenniferAlbarrán, María IsabelValle, SandraMuñoz, JavierMartínez-González, SoniaBlanco-Aparicio, CarmenPastor, JoaquínSerrano, ManuelSainz, BrunoCancer stem cellsCompound libraryLysosomal membrane permeabilizationPancreatic ductal adenocarcinomaPatient-derived xenograftsMedicinaDespite significant efforts to improve pancreatic ductal adenocarcinoma (PDAC) clinical outcomes, overall survival remains dismal. The poor response to current therapies is partly due to the existence of pancreatic cancer stem cells (PaCSCs), which are efficient drivers of PDAC tumorigenesis, metastasis and relapse. To find new therapeutic agents that could efficiently kill PaCSCs, we screened a chemical library of 680 compounds for candidate small molecules with anti-CSC activity, and identified two compounds of a specific chemical series with potent activity in vitro and in vivo against patient-derived xenograft (PDX) cultures. The anti-CSC mechanism of action of this specific chemical series was found to rely on induction of lysosomal membrane permeabilization (LMP), which is likely associated with the increased lysosomal mass observed in PaCSCs. Using the well characterized LMP-inducer siramesine as a tool molecule, we show elimination of the PaCSC population in mice implanted with tumors from two PDX models. Collectively, our approach identified lysosomal disruption as a promising anti-CSC therapeutic strategy for PDAC.This study was financially supported by a Ramón y Cajal Merit Award (RYC-2012-12104) from the Ministerio de Economía y Competitividad, Spain (B.S.Jr.); funding fromThe Fero Foundation (B.S.Jr.); a Coordinated grant from the Fundación Asociación Española Contra el Cáncer (AECC) GC16173694BARB (B.S.,Jr.); Fondo de Investigaciones Sanitarias (FIS) grant PI15/01507 and PI18/00757 (B.S.,Jr.), (cofinanced through Fondo Europeo de Desarrollo Regional (FEDER) “Una manera de hacer Europa”). ETP activities were supported by funds of The Spanish National Cancer Research Centre (CNIO).Work in the laboratory of M.S. was funded by the CNIO, the IRB and “laCaixa” Foundation, and by grants from the Spanish Ministry of Economy co-funded by the European Regional Development Fund (ERDF) (SAF2017-82613-R), the European Research Council (ERC-2014-AdG/669622) and, Secretaria d’Universitats i Recerca del Departament d’Empresa i Coneixement of Catalonia (Grup de Recerca consolidat 2017 SGR 282).MDPI, Basel, SwitzerlandDepartamento de BioquímicaFacultad de MedicinaInstituto de Investigaciones Biomédicas "Alberto Sols" (IIBM)20202020-07-04research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10486/694718https://dx.doi.org/10.3390/cancers12071790reponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:Universidad Autónoma de MadridInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:repositorio.uam.es:10486/6947182026-06-23T12:46:27Z
dc.title.none.fl_str_mv Induction of lysosome membrane permeabilization as a therapeutic strategy to target pancreatic cancer stem cells
title Induction of lysosome membrane permeabilization as a therapeutic strategy to target pancreatic cancer stem cells
spellingShingle Induction of lysosome membrane permeabilization as a therapeutic strategy to target pancreatic cancer stem cells
Cash, Timothy P.
Cancer stem cells
Compound library
Lysosomal membrane permeabilization
Pancreatic ductal adenocarcinoma
Patient-derived xenografts
Medicina
title_short Induction of lysosome membrane permeabilization as a therapeutic strategy to target pancreatic cancer stem cells
title_full Induction of lysosome membrane permeabilization as a therapeutic strategy to target pancreatic cancer stem cells
title_fullStr Induction of lysosome membrane permeabilization as a therapeutic strategy to target pancreatic cancer stem cells
title_full_unstemmed Induction of lysosome membrane permeabilization as a therapeutic strategy to target pancreatic cancer stem cells
title_sort Induction of lysosome membrane permeabilization as a therapeutic strategy to target pancreatic cancer stem cells
dc.creator.none.fl_str_mv Cash, Timothy P.
Alcalá, Sonia
Rico-Ferreira, María Del Rosario
Hernández-Encinas, Elena
García, Jennifer
Albarrán, María Isabel
Valle, Sandra
Muñoz, Javier
Martínez-González, Sonia
Blanco-Aparicio, Carmen
Pastor, Joaquín
Serrano, Manuel
Sainz, Bruno
author Cash, Timothy P.
author_facet Cash, Timothy P.
Alcalá, Sonia
Rico-Ferreira, María Del Rosario
Hernández-Encinas, Elena
García, Jennifer
Albarrán, María Isabel
Valle, Sandra
Muñoz, Javier
Martínez-González, Sonia
Blanco-Aparicio, Carmen
Pastor, Joaquín
Serrano, Manuel
Sainz, Bruno
author_role author
author2 Alcalá, Sonia
Rico-Ferreira, María Del Rosario
Hernández-Encinas, Elena
García, Jennifer
Albarrán, María Isabel
Valle, Sandra
Muñoz, Javier
Martínez-González, Sonia
Blanco-Aparicio, Carmen
Pastor, Joaquín
Serrano, Manuel
Sainz, Bruno
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Departamento de Bioquímica
Facultad de Medicina
Instituto de Investigaciones Biomédicas "Alberto Sols" (IIBM)
dc.subject.none.fl_str_mv Cancer stem cells
Compound library
Lysosomal membrane permeabilization
Pancreatic ductal adenocarcinoma
Patient-derived xenografts
Medicina
topic Cancer stem cells
Compound library
Lysosomal membrane permeabilization
Pancreatic ductal adenocarcinoma
Patient-derived xenografts
Medicina
description Despite significant efforts to improve pancreatic ductal adenocarcinoma (PDAC) clinical outcomes, overall survival remains dismal. The poor response to current therapies is partly due to the existence of pancreatic cancer stem cells (PaCSCs), which are efficient drivers of PDAC tumorigenesis, metastasis and relapse. To find new therapeutic agents that could efficiently kill PaCSCs, we screened a chemical library of 680 compounds for candidate small molecules with anti-CSC activity, and identified two compounds of a specific chemical series with potent activity in vitro and in vivo against patient-derived xenograft (PDX) cultures. The anti-CSC mechanism of action of this specific chemical series was found to rely on induction of lysosomal membrane permeabilization (LMP), which is likely associated with the increased lysosomal mass observed in PaCSCs. Using the well characterized LMP-inducer siramesine as a tool molecule, we show elimination of the PaCSC population in mice implanted with tumors from two PDX models. Collectively, our approach identified lysosomal disruption as a promising anti-CSC therapeutic strategy for PDAC.
publishDate 2020
dc.date.none.fl_str_mv 2020
2020-07-04
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10486/694718
https://dx.doi.org/10.3390/cancers12071790
url http://hdl.handle.net/10486/694718
https://dx.doi.org/10.3390/cancers12071790
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv MDPI, Basel, Switzerland
publisher.none.fl_str_mv MDPI, Basel, Switzerland
dc.source.none.fl_str_mv reponame:Biblos-e Archivo. Repositorio Institucional de la UAM
instname:Universidad Autónoma de Madrid
instname_str Universidad Autónoma de Madrid
reponame_str Biblos-e Archivo. Repositorio Institucional de la UAM
collection Biblos-e Archivo. Repositorio Institucional de la UAM
repository.name.fl_str_mv
repository.mail.fl_str_mv
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