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http://hdl.handle.net/2445/167806
Title: | Induction of Lysosome Membrane Permeabilization as a Therapeutic Strategy to Target Pancreatic Cancer Stem Cells |
Author: | 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 Marugán, Manuel Sainz, Bruno |
Keywords: | Cèl·lules mare Càncer de pàncrees Stem cells Pancreas cancer |
Issue Date: | 4-Jul-2020 |
Publisher: | MDPI |
Abstract: | 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. |
Note: | Reproducció del document publicat a: https://doi.org/10.3390/cancers12071790 |
It is part of: | Cancers, 2020, vol. 12, núm. 7, pag. 1790 |
URI: | http://hdl.handle.net/2445/167806 |
Related resource: | https://doi.org/10.3390/cancers12071790 |
Appears in Collections: | Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona)) Publicacions de projectes de recerca finançats per la UE |
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