Macropinocytosis Renders a Subset of Pancreatic Tumor Cells Resistant to mTOR Inhibition
Identifieur interne : 000118 ( an2020/Analysis ); précédent : 000117; suivant : 000119Macropinocytosis Renders a Subset of Pancreatic Tumor Cells Resistant to mTOR Inhibition
Auteurs : Evdokia Michalopoulou [Royaume-Uni] ; Francesca R. Auciello [Royaume-Uni] ; Vinay Bulusu [Royaume-Uni] ; David Strachan [Royaume-Uni] ; Andrew D. Campbell [Royaume-Uni] ; Jacqueline Tait-Mulder [Royaume-Uni] ; Saadia A. Karim [Royaume-Uni] ; Jennifer P. Morton [Royaume-Uni] ; Owen J. Sansom [Royaume-Uni] ; Jurre J. Kamphorst [Royaume-Uni]Source :
- Cell Reports [ 2211-1247 ] ; 2020.
Abstract
Pancreatic ductal adenocarcinoma (PDAC) features a near-universal mutation in
Url:
DOI: 10.1016/j.celrep.2020.01.080
PubMed: 32101748
PubMed Central: 7043007
Affiliations:
Links toward previous steps (curation, corpus...)
- to stream Pmc, to step Corpus: 000470
- to stream Pmc, to step Curation: 000470
- to stream Pmc, to step Checkpoint: 000111
- to stream Ncbi, to step Merge: 000F64
- to stream Ncbi, to step Curation: 000F64
- to stream Ncbi, to step Checkpoint: 000F64
- to stream Main, to step Merge: 000118
- to stream Main, to step Curation: 000118
- to stream Main, to step Exploration: 000118
- to stream an2020, to step Extraction: 000118
Links to Exploration step
PMC:7043007Le document en format XML
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Auciello</name><affiliation wicri:level="1"><nlm:aff id="aff1">Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD</wicri:regionArea><wicri:noRegion>Glasgow G61 1BD</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:aff id="aff2">Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH</wicri:regionArea><orgName type="university">Université de Glasgow</orgName><placeName><settlement type="city">Glasgow</settlement><region type="country">Écosse</region></placeName></affiliation></author><author><name sortKey="Bulusu, Vinay" sort="Bulusu, Vinay" uniqKey="Bulusu V" first="Vinay" last="Bulusu">Vinay Bulusu</name><affiliation wicri:level="1"><nlm:aff id="aff1">Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD</wicri:regionArea><wicri:noRegion>Glasgow G61 1BD</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:aff id="aff2">Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH</wicri:regionArea><orgName type="university">Université de Glasgow</orgName><placeName><settlement type="city">Glasgow</settlement><region type="country">Écosse</region></placeName></affiliation></author><author><name sortKey="Strachan, David" sort="Strachan, David" uniqKey="Strachan D" first="David" last="Strachan">David Strachan</name><affiliation wicri:level="1"><nlm:aff id="aff1">Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD</wicri:regionArea><wicri:noRegion>Glasgow G61 1BD</wicri:noRegion></affiliation></author><author><name sortKey="Campbell, Andrew D" sort="Campbell, Andrew D" uniqKey="Campbell A" first="Andrew D." last="Campbell">Andrew D. 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Auciello</name><affiliation wicri:level="1"><nlm:aff id="aff1">Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD</wicri:regionArea><wicri:noRegion>Glasgow G61 1BD</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:aff id="aff2">Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH</wicri:regionArea><orgName type="university">Université de Glasgow</orgName><placeName><settlement type="city">Glasgow</settlement><region type="country">Écosse</region></placeName></affiliation></author><author><name sortKey="Bulusu, Vinay" sort="Bulusu, Vinay" uniqKey="Bulusu V" first="Vinay" last="Bulusu">Vinay Bulusu</name><affiliation wicri:level="1"><nlm:aff id="aff1">Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD</wicri:regionArea><wicri:noRegion>Glasgow G61 1BD</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:aff id="aff2">Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH</wicri:regionArea><orgName type="university">Université de Glasgow</orgName><placeName><settlement type="city">Glasgow</settlement><region type="country">Écosse</region></placeName></affiliation></author><author><name sortKey="Strachan, David" sort="Strachan, David" uniqKey="Strachan D" first="David" last="Strachan">David Strachan</name><affiliation wicri:level="1"><nlm:aff id="aff1">Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD</wicri:regionArea><wicri:noRegion>Glasgow G61 1BD</wicri:noRegion></affiliation></author><author><name sortKey="Campbell, Andrew D" sort="Campbell, Andrew D" uniqKey="Campbell A" first="Andrew D." last="Campbell">Andrew D. Campbell</name><affiliation wicri:level="1"><nlm:aff id="aff1">Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD</wicri:regionArea><wicri:noRegion>Glasgow G61 1BD</wicri:noRegion></affiliation></author><author><name sortKey="Tait Mulder, Jacqueline" sort="Tait Mulder, Jacqueline" uniqKey="Tait Mulder J" first="Jacqueline" last="Tait-Mulder">Jacqueline Tait-Mulder</name><affiliation wicri:level="1"><nlm:aff id="aff1">Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD</wicri:regionArea><wicri:noRegion>Glasgow G61 1BD</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:aff id="aff2">Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH</wicri:regionArea><orgName type="university">Université de Glasgow</orgName><placeName><settlement type="city">Glasgow</settlement><region type="country">Écosse</region></placeName></affiliation></author><author><name sortKey="Karim, Saadia A" sort="Karim, Saadia A" uniqKey="Karim S" first="Saadia A." last="Karim">Saadia A. Karim</name><affiliation wicri:level="1"><nlm:aff id="aff1">Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD</wicri:regionArea><wicri:noRegion>Glasgow G61 1BD</wicri:noRegion></affiliation></author><author><name sortKey="Morton, Jennifer P" sort="Morton, Jennifer P" uniqKey="Morton J" first="Jennifer P." last="Morton">Jennifer P. Morton</name><affiliation wicri:level="1"><nlm:aff id="aff1">Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD</wicri:regionArea><wicri:noRegion>Glasgow G61 1BD</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:aff id="aff2">Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH</wicri:regionArea><orgName type="university">Université de Glasgow</orgName><placeName><settlement type="city">Glasgow</settlement><region type="country">Écosse</region></placeName></affiliation></author><author><name sortKey="Sansom, Owen J" sort="Sansom, Owen J" uniqKey="Sansom O" first="Owen J." last="Sansom">Owen J. Sansom</name><affiliation wicri:level="1"><nlm:aff id="aff1">Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD</wicri:regionArea><wicri:noRegion>Glasgow G61 1BD</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:aff id="aff2">Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH</wicri:regionArea><orgName type="university">Université de Glasgow</orgName><placeName><settlement type="city">Glasgow</settlement><region type="country">Écosse</region></placeName></affiliation></author><author><name sortKey="Kamphorst, Jurre J" sort="Kamphorst, Jurre J" uniqKey="Kamphorst J" first="Jurre J." last="Kamphorst">Jurre J. Kamphorst</name><affiliation wicri:level="1"><nlm:aff id="aff1">Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD</wicri:regionArea><wicri:noRegion>Glasgow G61 1BD</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:aff id="aff2">Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH</wicri:regionArea><orgName type="university">Université de Glasgow</orgName><placeName><settlement type="city">Glasgow</settlement><region type="country">Écosse</region></placeName></affiliation></author></analytic><series><title level="j">Cell Reports</title><idno type="eISSN">2211-1247</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Summary</title><p>Pancreatic ductal adenocarcinoma (PDAC) features a near-universal mutation in <italic>KRAS</italic>. Additionally, the tumor suppressor <italic>PTEN</italic> is lost in ∼10% of patients, and in mouse models, this dramatically accelerates tumor progression. While oncogenic KRAS and phosphatidylinositol 3-kinase (PI3K) cause divergent metabolic phenotypes individually, how they synergize to promote tumor metabolic alterations and dependencies remains unknown. We show that in KRAS-driven murine PDAC cells, loss of <italic>Pten</italic> strongly enhances both mTOR signaling and macropinocytosis. Protein scavenging alleviates sensitivity to mTOR inhibition by rescuing AKT phosphorylation at serine 473 and consequently cell proliferation. Combined inhibition of mTOR and lysosomal processing of internalized protein eliminates the macropinocytosis-mediated resistance. Our results indicate that mTORC2, rather than mTORC1, is an important regulator of protein scavenging and that protein-mediated resistance could explain the lack of effectiveness of mTOR inhibitors in certain genetic backgrounds. Concurrent inhibition of mTOR and protein scavenging might be a valuable therapeutic approach.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Bar Sagi, D" uniqKey="Bar Sagi D">D. Bar-Sagi</name></author><author><name sortKey="Feramisco, J R" uniqKey="Feramisco J">J.R. Feramisco</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bloomfield, G" uniqKey="Bloomfield G">G. Bloomfield</name></author><author><name sortKey="Traynor, D" uniqKey="Traynor D">D. Traynor</name></author><author><name sortKey="Sander, S P" uniqKey="Sander S">S.P. Sander</name></author><author><name sortKey="Veltman, D M" uniqKey="Veltman D">D.M. 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Karim</name><name sortKey="Michalopoulou, Evdokia" sort="Michalopoulou, Evdokia" uniqKey="Michalopoulou E" first="Evdokia" last="Michalopoulou">Evdokia Michalopoulou</name><name sortKey="Morton, Jennifer P" sort="Morton, Jennifer P" uniqKey="Morton J" first="Jennifer P." last="Morton">Jennifer P. Morton</name><name sortKey="Morton, Jennifer P" sort="Morton, Jennifer P" uniqKey="Morton J" first="Jennifer P." last="Morton">Jennifer P. Morton</name><name sortKey="Sansom, Owen J" sort="Sansom, Owen J" uniqKey="Sansom O" first="Owen J." last="Sansom">Owen J. Sansom</name><name sortKey="Sansom, Owen J" sort="Sansom, Owen J" uniqKey="Sansom O" first="Owen J." last="Sansom">Owen J. Sansom</name><name sortKey="Strachan, David" sort="Strachan, David" uniqKey="Strachan D" first="David" last="Strachan">David Strachan</name><name sortKey="Tait Mulder, Jacqueline" sort="Tait Mulder, Jacqueline" uniqKey="Tait Mulder J" first="Jacqueline" last="Tait-Mulder">Jacqueline Tait-Mulder</name><name sortKey="Tait Mulder, Jacqueline" sort="Tait Mulder, Jacqueline" uniqKey="Tait Mulder J" first="Jacqueline" last="Tait-Mulder">Jacqueline Tait-Mulder</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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