Macropinocytosis Renders a Subset of Pancreatic Tumor Cells Resistant to mTOR Inhibition
Identifieur interne : 000470 ( Pmc/Curation ); précédent : 000469; suivant : 000471Macropinocytosis 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
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PMC:7043007Le document en format XML
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<author><name sortKey="Auciello, Francesca R" sort="Auciello, Francesca R" uniqKey="Auciello F" first="Francesca R." last="Auciello">Francesca R. Auciello</name>
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<author><name sortKey="Strachan, David" sort="Strachan, David" uniqKey="Strachan D" first="David" last="Strachan">David Strachan</name>
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<author><name sortKey="Tait Mulder, Jacqueline" sort="Tait Mulder, Jacqueline" uniqKey="Tait Mulder J" first="Jacqueline" last="Tait-Mulder">Jacqueline Tait-Mulder</name>
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<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><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>
</affiliation>
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<author><name sortKey="Karim, Saadia A" sort="Karim, Saadia A" uniqKey="Karim S" first="Saadia A." last="Karim">Saadia A. Karim</name>
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<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD</wicri:regionArea>
</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>
</affiliation>
<affiliation wicri:level="1"><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>
</affiliation>
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<author><name sortKey="Sansom, Owen J" sort="Sansom, Owen J" uniqKey="Sansom O" first="Owen J." last="Sansom">Owen J. Sansom</name>
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<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><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>
</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>
</affiliation>
<affiliation wicri:level="1"><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>
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<series><title level="j">Cell Reports</title>
<idno type="eISSN">2211-1247</idno>
<imprint><date when="2020">2020</date>
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<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>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Cell Rep</journal-id>
<journal-id journal-id-type="iso-abbrev">Cell Rep</journal-id>
<journal-title-group><journal-title>Cell Reports</journal-title>
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<issn pub-type="epub">2211-1247</issn>
<publisher><publisher-name>Cell Press</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">32101748</article-id>
<article-id pub-id-type="pmc">7043007</article-id>
<article-id pub-id-type="publisher-id">S2211-1247(20)30105-4</article-id>
<article-id pub-id-type="doi">10.1016/j.celrep.2020.01.080</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Macropinocytosis Renders a Subset of Pancreatic Tumor Cells Resistant to mTOR Inhibition</article-title>
</title-group>
<contrib-group><contrib contrib-type="author" id="au1"><name><surname>Michalopoulou</surname>
<given-names>Evdokia</given-names>
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<xref rid="aff1" ref-type="aff">1</xref>
<xref rid="aff2" ref-type="aff">2</xref>
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<given-names>Francesca R.</given-names>
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<xref rid="aff1" ref-type="aff">1</xref>
<xref rid="aff2" ref-type="aff">2</xref>
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<given-names>Vinay</given-names>
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<xref rid="aff1" ref-type="aff">1</xref>
<xref rid="aff2" ref-type="aff">2</xref>
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<given-names>David</given-names>
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<xref rid="aff1" ref-type="aff">1</xref>
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<given-names>Andrew D.</given-names>
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<xref rid="aff1" ref-type="aff">1</xref>
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<given-names>Jacqueline</given-names>
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<xref rid="aff1" ref-type="aff">1</xref>
<xref rid="aff2" ref-type="aff">2</xref>
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<given-names>Saadia A.</given-names>
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<xref rid="aff2" ref-type="aff">2</xref>
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<given-names>Owen J.</given-names>
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<xref rid="aff2" ref-type="aff">2</xref>
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<given-names>Jurre J.</given-names>
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<email>jurre.kamphorst@glasgow.ac.uk</email>
<xref rid="aff1" ref-type="aff">1</xref>
<xref rid="aff2" ref-type="aff">2</xref>
<xref rid="fn1" ref-type="fn">3</xref>
<xref rid="fn2" ref-type="fn">4</xref>
<xref rid="cor1" ref-type="corresp">∗</xref>
</contrib>
</contrib-group>
<aff id="aff1"><label>1</label>
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK</aff>
<aff id="aff2"><label>2</label>
Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH, UK</aff>
<author-notes><corresp id="cor1"><label>∗</label>
Corresponding author <email>jurre.kamphorst@glasgow.ac.uk</email>
</corresp>
<fn id="fn1"><label>3</label>
<p id="ntpara0010">Present address: Rheos Medicines, 38 Sidney Street, Cambridge, MA 02139, USA</p>
</fn>
<fn id="fn2"><label>4</label>
<p id="ntpara0015">Lead Contact</p>
</fn>
</author-notes>
<pub-date pub-type="pmc-release"><day>25</day>
<month>2</month>
<year>2020</year>
</pub-date>
<pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="collection"><day>25</day>
<month>2</month>
<year>2020</year>
</pub-date>
<pub-date pub-type="epub"><day>25</day>
<month>2</month>
<year>2020</year>
</pub-date>
<volume>30</volume>
<issue>8</issue>
<fpage>2729</fpage>
<lpage>2742.e4</lpage>
<history><date date-type="received"><day>19</day>
<month>5</month>
<year>2019</year>
</date>
<date date-type="rev-recd"><day>14</day>
<month>10</month>
<year>2019</year>
</date>
<date date-type="accepted"><day>21</day>
<month>1</month>
<year>2020</year>
</date>
</history>
<permissions><copyright-statement>© 2020 The Author(s)</copyright-statement>
<copyright-year>2020</copyright-year>
<license license-type="CC BY" xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).</license-p>
</license>
</permissions>
<abstract id="abs0010"><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>
</abstract>
<abstract abstract-type="graphical" id="abs0015"><title>Graphical Abstract</title>
<fig id="undfig1" position="anchor"><graphic xlink:href="fx1"></graphic>
</fig>
</abstract>
<abstract abstract-type="author-highlights" id="abs0020"><title>Highlights</title>
<p><list list-type="simple" id="ulist0010"><list-item id="u0010"><label>•</label>
<p id="p0010">PTEN loss increases scavenging, conferring resistance to mTOR inhibition in PDAC</p>
</list-item>
<list-item id="u0015"><label>•</label>
<p id="p0015">mTORC2 selectively regulates macropinocytosis independently of its kinase activity</p>
</list-item>
<list-item id="u0020"><label>•</label>
<p id="p0020">Protein scavenging restores pAkt serine 473, leading to recovery of proliferation</p>
</list-item>
<list-item id="u0025"><label>•</label>
<p id="p0025">Lysosomal blockade eliminates the protein-mediated resistance to mTOR inhibition</p>
</list-item>
</list>
</p>
</abstract>
<abstract abstract-type="teaser" id="abs0025"><p>Michalopoulou et al. show that in pancreatic cancer cells with oncogenic KRAS and PTEN loss, scavenging of extracellular protein provides resistance against mTOR inhibition. Protein scavenging circumvents mTORC2 signaling by rescuing AKT phosphorylation. Additional treatment with AKT or lysosomal inhibitors strongly potentiates the effect of mTOR inhibitors.</p>
</abstract>
<kwd-group id="kwrds0010"><title>Keywords</title>
<kwd>AKT</kwd>
<kwd>cancer metabolism</kwd>
<kwd>macropinocytosis</kwd>
<kwd>metabolic scavenging</kwd>
<kwd>mTORC2</kwd>
<kwd>pancreatic ductal adenocarcinoma</kwd>
</kwd-group>
</article-meta>
<notes><p id="misc0010">Published: February 25, 2020</p>
</notes>
</front>
</pmc>
</record>
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