2026-07-21T07:18:04Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/110092024-11-29T15:36:01Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Cash, Timothy P author Alcalá, Sonia author Rico-Ferreira, María Del Rosario author Hernández-Encinas, Elena author García, Jennifer author Albarrán, María Isabel author Valle, Sandra author Serrano, Manuel author Sainz, Bruno author Blanco-Aparicio, Carmen author Pastor Fernandez, Joaquin author Martinez, Sonia author Munoz, Javier author 2020-07-04 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. Cancers (Basel) . 2020;12(7):1790 10.3390/cancers12071790 2072-6694 Cancers 32635473 http://hdl.handle.net/20.500.12105/11009 DEATH PATHWAY DISRUPTION METABOLISM SIRAMESINE INHIBITORS SURVIVAL Induction of Lysosome Membrane Permeabilization as a Therapeutic Strategy to Target Pancreatic Cancer Stem Cells.