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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| Veröffentlicht in: | Cancers 2020-07, Vol.12 (7), p.1790 |
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| creator | 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 |
| 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. |
| doi_str_mv | 10.3390/cancers12071790 |
| format | Article |
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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.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers12071790</identifier><identifier>PMID: 32635473</identifier><language>eng</language><publisher>Basel: MDPI AG</publisher><subject>Adenocarcinoma ; Apoptosis ; Cancer therapies ; Drug dosages ; Kinases ; Metastases ; Metastasis ; Pancreatic cancer ; Population ; Spheres ; Stem cell transplantation ; Stem cells ; Tumorigenesis ; Tumors ; Xenografts</subject><ispartof>Cancers, 2020-07, Vol.12 (7), p.1790</ispartof><rights>2020. This work is licensed under http://creativecommons.org/licenses/by/3.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 by the authors. 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c398t-1b679fb45dd34c7332aa4f0021f41acd4ee1bd3a6fc0d524fb34b68434b278f83</citedby><cites>FETCH-LOGICAL-c398t-1b679fb45dd34c7332aa4f0021f41acd4ee1bd3a6fc0d524fb34b68434b278f83</cites><orcidid>0000-0002-3249-6595 ; 0000-0003-3288-3496 ; 0000-0003-2230-7794 ; 0000-0003-4829-7651 ; 0000-0002-7555-9357 ; 0000-0001-7177-9312</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407272/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407272/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids></links><search><creatorcontrib>Cash, Timothy P.</creatorcontrib><creatorcontrib>Alcalá, Sonia</creatorcontrib><creatorcontrib>Rico-Ferreira, María del Rosario</creatorcontrib><creatorcontrib>Hernández-Encinas, Elena</creatorcontrib><creatorcontrib>García, Jennifer</creatorcontrib><creatorcontrib>Albarrán, María Isabel</creatorcontrib><creatorcontrib>Valle, Sandra</creatorcontrib><creatorcontrib>Muñoz, Javier</creatorcontrib><creatorcontrib>Martínez-González, Sonia</creatorcontrib><creatorcontrib>Blanco-Aparicio, Carmen</creatorcontrib><creatorcontrib>Pastor, Joaquín</creatorcontrib><creatorcontrib>Serrano, Manuel</creatorcontrib><creatorcontrib>Sainz, Bruno</creatorcontrib><title>Induction of Lysosome Membrane Permeabilization as a Therapeutic Strategy to Target Pancreatic Cancer Stem Cells</title><title>Cancers</title><description>Despite significant efforts to improve pancreatic ductal adenocarcinoma (PDAC) clinical outcomes, overall survival remains dismal. 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Collectively, our approach identified lysosomal disruption as a promising anti-CSC therapeutic strategy for PDAC.</description><subject>Adenocarcinoma</subject><subject>Apoptosis</subject><subject>Cancer therapies</subject><subject>Drug dosages</subject><subject>Kinases</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Pancreatic cancer</subject><subject>Population</subject><subject>Spheres</subject><subject>Stem cell transplantation</subject><subject>Stem cells</subject><subject>Tumorigenesis</subject><subject>Tumors</subject><subject>Xenografts</subject><issn>2072-6694</issn><issn>2072-6694</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkU1LxDAQhoMoKurZa8CLl3Xz1aa9CLL4BSsKrucwTSdrpW3WpBXWX29cRdQ5zAzMw8s7M4Qcc3YmZcmmFnqLIXLBNNcl2yL7qROTPC_V9q9-jxzF-MJSSMl1rnfJnhS5zJSW-2R129ejHRrfU-_ofB199B3SO-yqAD3SBwwdQtW0zTtsKIgU6OIZA6xwHBpLH4cAAy7XdPB0AWGJA31IxgLC53S28Zgg7OgM2zYekh0HbcSj73pAnq4uF7Obyfz--nZ2MZ9YWRbDhFe5Ll2lsrqWymopBYByjAnuFAdbK0Re1RJyZ1mdCeUqqaq8UCkLXbhCHpDzL93VWHVYW-yTz9asQtNBWBsPjfk76Ztns_RvRqt0OC2SwOm3QPCvI8bBdE20aYV0Fj9GI5TgKmfZBj35h774MfRpvQ2VFYyXOlHTL8oGH2NA92OGM_P5UPPvofIDyeSVHQ</recordid><startdate>20200704</startdate><enddate>20200704</enddate><creator>Cash, Timothy P.</creator><creator>Alcalá, Sonia</creator><creator>Rico-Ferreira, María del Rosario</creator><creator>Hernández-Encinas, Elena</creator><creator>García, Jennifer</creator><creator>Albarrán, María Isabel</creator><creator>Valle, Sandra</creator><creator>Muñoz, Javier</creator><creator>Martínez-González, Sonia</creator><creator>Blanco-Aparicio, Carmen</creator><creator>Pastor, Joaquín</creator><creator>Serrano, Manuel</creator><creator>Sainz, Bruno</creator><general>MDPI AG</general><general>MDPI</general><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7TO</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-3249-6595</orcidid><orcidid>https://orcid.org/0000-0003-3288-3496</orcidid><orcidid>https://orcid.org/0000-0003-2230-7794</orcidid><orcidid>https://orcid.org/0000-0003-4829-7651</orcidid><orcidid>https://orcid.org/0000-0002-7555-9357</orcidid><orcidid>https://orcid.org/0000-0001-7177-9312</orcidid></search><sort><creationdate>20200704</creationdate><title>Induction of Lysosome Membrane Permeabilization as a Therapeutic Strategy to Target Pancreatic Cancer Stem Cells</title><author>Cash, Timothy P. ; 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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. 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| subjects | Adenocarcinoma Apoptosis Cancer therapies Drug dosages Kinases Metastases Metastasis Pancreatic cancer Population Spheres Stem cell transplantation Stem cells Tumorigenesis Tumors Xenografts |
| title | Induction of Lysosome Membrane Permeabilization as a Therapeutic Strategy to Target Pancreatic Cancer Stem Cells |
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