Requirement for epithelial p38α in KRAS-driven lung tumor progression
Malignant transformation entails important changes in the control of cell proliferation through the rewiring of selected signaling pathways. Cancer cells then become very dependent on the proper function of those pathways, and their inhibition offers therapeutic opportunities. Here we identify the s...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2020-02, Vol.117 (5), p.2588-2596 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Vitos-Faleato, Jessica Real, Sebastián M. Gutierrez-Prat, Nuria Villanueva, Alberto Llonch, Elisabet Drosten, Matthias Barbacid, Mariano Nebreda, Angel R. |
| description | Malignant transformation entails important changes in the control of cell proliferation through the rewiring of selected signaling pathways. Cancer cells then become very dependent on the proper function of those pathways, and their inhibition offers therapeutic opportunities. Here we identify the stress kinase p38α as a nononcogenic signaling molecule that enables the progression of KrasG12V-driven lung cancer. We demonstrate in vivo that, despite acting as a tumor suppressor in healthy alveolar progenitor cells, p38α contributes to the proliferation and malignization of lung cancer epithelial cells. We show that high expression levels of p38α correlate with poor survival in lung adenocarcinoma patients, and that genetic or chemical inhibition of p38α halts tumor growth in lung cancer mouse models. Moreover, we reveal a lung cancer epithelial cell-autonomous function for p38α promoting the expression of TIMP-1, which in turn stimulates cell proliferation in an autocrine manner. Altogether, our results suggest that epithelial p38α promotes KrasG12V-driven lung cancer progression via maintenance of cellular self-growth stimulatory signals. |
| doi_str_mv | 10.1073/pnas.1921404117 |
| format | Article |
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Cancer cells then become very dependent on the proper function of those pathways, and their inhibition offers therapeutic opportunities. Here we identify the stress kinase p38α as a nononcogenic signaling molecule that enables the progression of KrasG12V-driven lung cancer. We demonstrate in vivo that, despite acting as a tumor suppressor in healthy alveolar progenitor cells, p38α contributes to the proliferation and malignization of lung cancer epithelial cells. We show that high expression levels of p38α correlate with poor survival in lung adenocarcinoma patients, and that genetic or chemical inhibition of p38α halts tumor growth in lung cancer mouse models. Moreover, we reveal a lung cancer epithelial cell-autonomous function for p38α promoting the expression of TIMP-1, which in turn stimulates cell proliferation in an autocrine manner. Altogether, our results suggest that epithelial p38α promotes KrasG12V-driven lung cancer progression via maintenance of cellular self-growth stimulatory signals.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1921404117</identifier><identifier>PMID: 31969449</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Adenocarcinoma ; Alveoli ; Animal models ; Autocrine signalling ; Biological Sciences ; Cell growth ; Cell proliferation ; Cells (biology) ; Epithelial cells ; Genetic transformation ; K-Ras protein ; Kinases ; Lung cancer ; Organic chemistry ; Progenitor cells ; Rewiring ; Signal transduction ; Signaling ; Stem cells ; Tissue inhibitor of metalloproteinase 1 ; Tumor suppressor genes ; Tumors</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2020-02, Vol.117 (5), p.2588-2596</ispartof><rights>Copyright National Academy of Sciences Feb 4, 2020</rights><rights>2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c443t-2f1187e9020cc313fefad29eee0231ba9c824846bee1c3ee1cbf27d81b6f0d7a3</citedby><cites>FETCH-LOGICAL-c443t-2f1187e9020cc313fefad29eee0231ba9c824846bee1c3ee1cbf27d81b6f0d7a3</cites><orcidid>0000-0003-3979-2597 ; 0000-0002-3205-456X ; 0000-0001-6717-8434 ; 0000-0002-7631-4060 ; 0000-0002-1480-2624 ; 0000-0002-9016-4695 ; 0000-0001-7286-2724</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/26928859$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/26928859$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27923,27924,53790,53792,58016,58249</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31969449$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Vitos-Faleato, Jessica</creatorcontrib><creatorcontrib>Real, Sebastián M.</creatorcontrib><creatorcontrib>Gutierrez-Prat, Nuria</creatorcontrib><creatorcontrib>Villanueva, Alberto</creatorcontrib><creatorcontrib>Llonch, Elisabet</creatorcontrib><creatorcontrib>Drosten, Matthias</creatorcontrib><creatorcontrib>Barbacid, Mariano</creatorcontrib><creatorcontrib>Nebreda, Angel R.</creatorcontrib><title>Requirement for epithelial p38α in KRAS-driven lung tumor progression</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Malignant transformation entails important changes in the control of cell proliferation through the rewiring of selected signaling pathways. Cancer cells then become very dependent on the proper function of those pathways, and their inhibition offers therapeutic opportunities. Here we identify the stress kinase p38α as a nononcogenic signaling molecule that enables the progression of KrasG12V-driven lung cancer. We demonstrate in vivo that, despite acting as a tumor suppressor in healthy alveolar progenitor cells, p38α contributes to the proliferation and malignization of lung cancer epithelial cells. We show that high expression levels of p38α correlate with poor survival in lung adenocarcinoma patients, and that genetic or chemical inhibition of p38α halts tumor growth in lung cancer mouse models. Moreover, we reveal a lung cancer epithelial cell-autonomous function for p38α promoting the expression of TIMP-1, which in turn stimulates cell proliferation in an autocrine manner. Altogether, our results suggest that epithelial p38α promotes KrasG12V-driven lung cancer progression via maintenance of cellular self-growth stimulatory signals.</description><subject>Adenocarcinoma</subject><subject>Alveoli</subject><subject>Animal models</subject><subject>Autocrine signalling</subject><subject>Biological Sciences</subject><subject>Cell growth</subject><subject>Cell proliferation</subject><subject>Cells (biology)</subject><subject>Epithelial cells</subject><subject>Genetic transformation</subject><subject>K-Ras protein</subject><subject>Kinases</subject><subject>Lung cancer</subject><subject>Organic chemistry</subject><subject>Progenitor cells</subject><subject>Rewiring</subject><subject>Signal transduction</subject><subject>Signaling</subject><subject>Stem cells</subject><subject>Tissue inhibitor of metalloproteinase 1</subject><subject>Tumor suppressor genes</subject><subject>Tumors</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNpdkU9v1DAQxS1ERZfCmRMoUi9c0o7_JLYvSFVFadVKSAXOlpNMtl4ldmonlfhYfBE-E15t2RYuM4f5zdN7eoS8o3BCQfLTydt0QjWjAgSl8gVZUdC0rIWGl2QFwGSpBBOH5HVKGwDQlYJX5JBTXWsh9Ipc3OL94iKO6OeiD7HAyc13ODg7FBNXv38VzhfXt2ffyi66B_TFsPh1MS9jRqcY1hFTcsG_IQe9HRK-fdxH5MfF5-_nl-XN1y9X52c3ZSsEn0vWU6okamDQtpzyHnvbMY2IwDhtrG4VE0rUDSJt-XY0PZOdok3dQyctPyKfdrrT0ozYtdl1tIOZohtt_GmCdebfi3d3Zh0ejASQVcWywMdHgRjuF0yzGV1qcRisx7Akw7gQjOm64hk9_g_dhCX6HC9Tlcj2pd4Knu6oNoaUIvZ7MxTMtiOz7cg8dZQ_PjzPsOf_lpKB9ztgk-YQ93dWa6ZUpfkfw8mYkg</recordid><startdate>20200204</startdate><enddate>20200204</enddate><creator>Vitos-Faleato, Jessica</creator><creator>Real, Sebastián M.</creator><creator>Gutierrez-Prat, Nuria</creator><creator>Villanueva, Alberto</creator><creator>Llonch, Elisabet</creator><creator>Drosten, Matthias</creator><creator>Barbacid, Mariano</creator><creator>Nebreda, Angel R.</creator><general>National Academy of Sciences</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-3979-2597</orcidid><orcidid>https://orcid.org/0000-0002-3205-456X</orcidid><orcidid>https://orcid.org/0000-0001-6717-8434</orcidid><orcidid>https://orcid.org/0000-0002-7631-4060</orcidid><orcidid>https://orcid.org/0000-0002-1480-2624</orcidid><orcidid>https://orcid.org/0000-0002-9016-4695</orcidid><orcidid>https://orcid.org/0000-0001-7286-2724</orcidid></search><sort><creationdate>20200204</creationdate><title>Requirement for epithelial p38α in KRAS-driven lung tumor progression</title><author>Vitos-Faleato, Jessica ; 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| subjects | Adenocarcinoma Alveoli Animal models Autocrine signalling Biological Sciences Cell growth Cell proliferation Cells (biology) Epithelial cells Genetic transformation K-Ras protein Kinases Lung cancer Organic chemistry Progenitor cells Rewiring Signal transduction Signaling Stem cells Tissue inhibitor of metalloproteinase 1 Tumor suppressor genes Tumors |
| title | Requirement for epithelial p38α in KRAS-driven lung tumor progression |
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