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Article

Induction of Lysosome Membrane Permeabilization as a Therapeutic Strategy to Target Pancreatic Cancer Stem Cells

1
Tumor Suppression Group, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain
2
Department of Cancer Biology, Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), 28029 Madrid, Spain
3
Department of Biochemistry, Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain
4
Chronic Diseases and Cancer, Area 3—Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain
5
Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain
6
Proteomics Unit–ProteoRed-Instituto de Salud Carlos III, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain
7
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain
8
Catalan Institution for Research and Advanced Studies (ICREA), 08028 Barcelona, Spain
*
Author to whom correspondence should be addressed.
Co-senior authors.
Cancers 2020, 12(7), 1790; https://doi.org/10.3390/cancers12071790
Received: 21 June 2020 / Revised: 1 July 2020 / Accepted: 2 July 2020 / Published: 4 July 2020
(This article belongs to the Special Issue Recent Advances in Pancreatic Ductal Adenocarcinoma)
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. View Full-Text
Keywords: compound library; cancer stem cells; pancreatic ductal adenocarcinoma; lysosomal membrane permeabilization; patient-derived xenografts compound library; cancer stem cells; pancreatic ductal adenocarcinoma; lysosomal membrane permeabilization; patient-derived xenografts
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MDPI and ACS Style

Cash, T.P.; Alcalá, S.; Rico-Ferreira, M.d.R.; Hernández-Encinas, E.; García, J.; Albarrán, M.I.; Valle, S.; Muñoz, J.; Martínez-González, S.; Blanco-Aparicio, C.; Pastor, J.; Serrano, M.; Sainz, B., Jr. Induction of Lysosome Membrane Permeabilization as a Therapeutic Strategy to Target Pancreatic Cancer Stem Cells. Cancers 2020, 12, 1790. https://doi.org/10.3390/cancers12071790

AMA Style

Cash TP, Alcalá S, Rico-Ferreira MdR, Hernández-Encinas E, García J, Albarrán MI, Valle S, Muñoz J, Martínez-González S, Blanco-Aparicio C, Pastor J, Serrano M, Sainz B Jr.. Induction of Lysosome Membrane Permeabilization as a Therapeutic Strategy to Target Pancreatic Cancer Stem Cells. Cancers. 2020; 12(7):1790. https://doi.org/10.3390/cancers12071790

Chicago/Turabian Style

Cash, Timothy P., Sonia Alcalá, María d.R. Rico-Ferreira, Elena Hernández-Encinas, Jennifer García, María I. Albarrán, Sandra Valle, Javier Muñoz, Sonia Martínez-González, Carmen Blanco-Aparicio, Joaquín Pastor, Manuel Serrano, and Bruno Sainz Jr. 2020. "Induction of Lysosome Membrane Permeabilization as a Therapeutic Strategy to Target Pancreatic Cancer Stem Cells" Cancers 12, no. 7: 1790. https://doi.org/10.3390/cancers12071790

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