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CCL3 predicts exceptional response to TGFβ inhibition in basal-like pancreatic cancer enriched in LIF-producing macrophages
The TGFβ receptor inhibitor galunisertib showed promising efficacy in patients with pancreatic ductal adenocarcinoma (PDAC) in the phase 2 H9H-MC-JBAJ study. Identifying biomarkers for this treatment remains essential. Baseline plasma levels of chemokine CCL3 were integrated with clinical outcomes i...
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| Published in: | NPJ precision oncology 2024-10, Vol.8 (1), p.246-15, Article 246 |
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| container_end_page | 15 |
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| container_title | NPJ precision oncology |
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| creator | Pietrobono, Silvia Bertolini, Monica De Vita, Veronica Sabbadini, Fabio Fazzini, Federica Frusteri, Cristina Scarlato, Enza Mangiameli, Domenico Quinzii, Alberto Casalino, Simona Zecchetto, Camilla Merz, Valeria Melisi, Davide |
| description | The TGFβ receptor inhibitor galunisertib showed promising efficacy in patients with pancreatic ductal adenocarcinoma (PDAC) in the phase 2 H9H-MC-JBAJ study. Identifying biomarkers for this treatment remains essential. Baseline plasma levels of chemokine CCL3 were integrated with clinical outcomes in PDAC patients treated with galunisertib plus gemcitabine (
n
= 104) or placebo plus gemcitabine (
n
= 52). High CCL3 was a poor prognostic factor in the placebo group (mOS 3.6 vs. 10.1 months;
p
|
| doi_str_mv | 10.1038/s41698-024-00742-3 |
| format | article |
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n
= 104) or placebo plus gemcitabine (
n
= 52). High CCL3 was a poor prognostic factor in the placebo group (mOS 3.6 vs. 10.1 months;
p
< 0.01) but a positive predictor for galunisertib (mOS 9.2 vs. 3.6 months;
p
< 0.01). Mechanistically, tumor-derived CCL3 activates Tgfβ signaling in macrophages, inducing their M2 phenotype and Lif secretion, sustaining a mesenchymal/basal-like ecotype. TGFβ inhibition redirects macrophage polarization to M1, reducing Lif and shifting PDAC cells to a more epithelial/classical phenotype, improving gemcitabine sensitivity. This study supports exploring TGFβ-targeting agents in PDAC with a mesenchymal/basal-like ecotype driven by high CCL3 levels.</description><identifier>ISSN: 2397-768X</identifier><identifier>EISSN: 2397-768X</identifier><identifier>DOI: 10.1038/s41698-024-00742-3</identifier><identifier>PMID: 39478186</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/67/1059/602 ; 692/4028/67/1504/1713 ; 692/53/2423 ; Biomarkers ; Cancer Research ; Cancer therapies ; Chemokines ; Gene Therapy ; Human Genetics ; Internal Medicine ; Medical prognosis ; Medicine ; Medicine & Public Health ; Metastasis ; Oncology ; Pancreatic cancer ; Signal transduction ; Tumors</subject><ispartof>NPJ precision oncology, 2024-10, Vol.8 (1), p.246-15, Article 246</ispartof><rights>The Author(s) 2024</rights><rights>2024. The Author(s).</rights><rights>The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>The Author(s) 2024 2024</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c378t-59e83242f6747cd4ceb227ddacaa56d86ac089ce668c80fe0aab9e080860f84c3</cites><orcidid>0000-0002-4031-7585</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/PMC11525688/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/3122863021?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27924,27925,37012,37013,44590,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39478186$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pietrobono, Silvia</creatorcontrib><creatorcontrib>Bertolini, Monica</creatorcontrib><creatorcontrib>De Vita, Veronica</creatorcontrib><creatorcontrib>Sabbadini, Fabio</creatorcontrib><creatorcontrib>Fazzini, Federica</creatorcontrib><creatorcontrib>Frusteri, Cristina</creatorcontrib><creatorcontrib>Scarlato, Enza</creatorcontrib><creatorcontrib>Mangiameli, Domenico</creatorcontrib><creatorcontrib>Quinzii, Alberto</creatorcontrib><creatorcontrib>Casalino, Simona</creatorcontrib><creatorcontrib>Zecchetto, Camilla</creatorcontrib><creatorcontrib>Merz, Valeria</creatorcontrib><creatorcontrib>Melisi, Davide</creatorcontrib><title>CCL3 predicts exceptional response to TGFβ inhibition in basal-like pancreatic cancer enriched in LIF-producing macrophages</title><title>NPJ precision oncology</title><addtitle>npj Precis. Onc</addtitle><addtitle>NPJ Precis Oncol</addtitle><description>The TGFβ receptor inhibitor galunisertib showed promising efficacy in patients with pancreatic ductal adenocarcinoma (PDAC) in the phase 2 H9H-MC-JBAJ study. Identifying biomarkers for this treatment remains essential. Baseline plasma levels of chemokine CCL3 were integrated with clinical outcomes in PDAC patients treated with galunisertib plus gemcitabine (
n
= 104) or placebo plus gemcitabine (
n
= 52). High CCL3 was a poor prognostic factor in the placebo group (mOS 3.6 vs. 10.1 months;
p
< 0.01) but a positive predictor for galunisertib (mOS 9.2 vs. 3.6 months;
p
< 0.01). Mechanistically, tumor-derived CCL3 activates Tgfβ signaling in macrophages, inducing their M2 phenotype and Lif secretion, sustaining a mesenchymal/basal-like ecotype. TGFβ inhibition redirects macrophage polarization to M1, reducing Lif and shifting PDAC cells to a more epithelial/classical phenotype, improving gemcitabine sensitivity. This study supports exploring TGFβ-targeting agents in PDAC with a mesenchymal/basal-like ecotype driven by high CCL3 levels.</description><subject>631/67/1059/602</subject><subject>692/4028/67/1504/1713</subject><subject>692/53/2423</subject><subject>Biomarkers</subject><subject>Cancer Research</subject><subject>Cancer therapies</subject><subject>Chemokines</subject><subject>Gene Therapy</subject><subject>Human Genetics</subject><subject>Internal Medicine</subject><subject>Medical prognosis</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metastasis</subject><subject>Oncology</subject><subject>Pancreatic cancer</subject><subject>Signal transduction</subject><subject>Tumors</subject><issn>2397-768X</issn><issn>2397-768X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNp9ks1u1DAUhSMEolXpC7BAltiwCfgvjrNCaMS0I43EpkjsrBv7ZsZDJg52pgKJp-JBeKZ6mlJaFqx85fPd42v7FMVLRt8yKvS7JJlqdEm5LCmtJS_Fk-KUi6Yua6W_PH1QnxTnKe0opUxXjCv1vDgRjaw10-q0-LlYrAUZIzpvp0Twu8Vx8mGAnkRMYxgSkimQq4vl71_ED1vf-qOcS9JCgr7s_VckIww2IkzeEptLjASH6O0W3RFcr5blGIM7WD9syB5sDOMWNpheFM866BOe361nxeflx6vFZbn-dLFafFiXVtR6KqsGteCSd6qWtXXSYst57RxYgEo5rcBS3VhUSltNO6QAbYNUU61op6UVZ8Vq9nUBdmaMfg_xhwngze1GiBsDMQ_fo5GNtlJBZSmrJBWiUUw0FXWKO2TYNtnr_ew1Hto9OovDFKF_ZPpYGfzWbMK1YazildI6O7y5c4jh2wHTZPY-Wex7GDAckhGMcyUrrmhGX_-D7sIh5s-ZKa0E5SxTfKbyw6YUsbufhlFzDIuZw2JyWMxtWIzITa8e3uO-5U80MiBmIGVp2GD8e_Z_bG8Ak4rL5w</recordid><startdate>20241030</startdate><enddate>20241030</enddate><creator>Pietrobono, Silvia</creator><creator>Bertolini, Monica</creator><creator>De Vita, Veronica</creator><creator>Sabbadini, Fabio</creator><creator>Fazzini, Federica</creator><creator>Frusteri, Cristina</creator><creator>Scarlato, Enza</creator><creator>Mangiameli, Domenico</creator><creator>Quinzii, Alberto</creator><creator>Casalino, Simona</creator><creator>Zecchetto, Camilla</creator><creator>Merz, Valeria</creator><creator>Melisi, Davide</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><general>Nature Portfolio</general><scope>C6C</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>NAPCQ</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-4031-7585</orcidid></search><sort><creationdate>20241030</creationdate><title>CCL3 predicts exceptional response to TGFβ inhibition in basal-like pancreatic cancer enriched in LIF-producing macrophages</title><author>Pietrobono, Silvia ; Bertolini, Monica ; De Vita, Veronica ; Sabbadini, Fabio ; Fazzini, Federica ; Frusteri, Cristina ; Scarlato, Enza ; Mangiameli, Domenico ; Quinzii, Alberto ; Casalino, Simona ; Zecchetto, Camilla ; Merz, Valeria ; Melisi, Davide</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c378t-59e83242f6747cd4ceb227ddacaa56d86ac089ce668c80fe0aab9e080860f84c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>631/67/1059/602</topic><topic>692/4028/67/1504/1713</topic><topic>692/53/2423</topic><topic>Biomarkers</topic><topic>Cancer Research</topic><topic>Cancer therapies</topic><topic>Chemokines</topic><topic>Gene Therapy</topic><topic>Human Genetics</topic><topic>Internal Medicine</topic><topic>Medical prognosis</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metastasis</topic><topic>Oncology</topic><topic>Pancreatic cancer</topic><topic>Signal transduction</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pietrobono, Silvia</creatorcontrib><creatorcontrib>Bertolini, Monica</creatorcontrib><creatorcontrib>De Vita, Veronica</creatorcontrib><creatorcontrib>Sabbadini, Fabio</creatorcontrib><creatorcontrib>Fazzini, Federica</creatorcontrib><creatorcontrib>Frusteri, Cristina</creatorcontrib><creatorcontrib>Scarlato, Enza</creatorcontrib><creatorcontrib>Mangiameli, Domenico</creatorcontrib><creatorcontrib>Quinzii, Alberto</creatorcontrib><creatorcontrib>Casalino, Simona</creatorcontrib><creatorcontrib>Zecchetto, Camilla</creatorcontrib><creatorcontrib>Merz, Valeria</creatorcontrib><creatorcontrib>Melisi, Davide</creatorcontrib><collection>Springer Open Access</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Nursing & Allied Health Premium</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>NPJ precision oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pietrobono, Silvia</au><au>Bertolini, Monica</au><au>De Vita, Veronica</au><au>Sabbadini, Fabio</au><au>Fazzini, Federica</au><au>Frusteri, Cristina</au><au>Scarlato, Enza</au><au>Mangiameli, Domenico</au><au>Quinzii, Alberto</au><au>Casalino, Simona</au><au>Zecchetto, Camilla</au><au>Merz, Valeria</au><au>Melisi, Davide</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>CCL3 predicts exceptional response to TGFβ inhibition in basal-like pancreatic cancer enriched in LIF-producing macrophages</atitle><jtitle>NPJ precision oncology</jtitle><stitle>npj Precis. Onc</stitle><addtitle>NPJ Precis Oncol</addtitle><date>2024-10-30</date><risdate>2024</risdate><volume>8</volume><issue>1</issue><spage>246</spage><epage>15</epage><pages>246-15</pages><artnum>246</artnum><issn>2397-768X</issn><eissn>2397-768X</eissn><abstract>The TGFβ receptor inhibitor galunisertib showed promising efficacy in patients with pancreatic ductal adenocarcinoma (PDAC) in the phase 2 H9H-MC-JBAJ study. Identifying biomarkers for this treatment remains essential. Baseline plasma levels of chemokine CCL3 were integrated with clinical outcomes in PDAC patients treated with galunisertib plus gemcitabine (
n
= 104) or placebo plus gemcitabine (
n
= 52). High CCL3 was a poor prognostic factor in the placebo group (mOS 3.6 vs. 10.1 months;
p
< 0.01) but a positive predictor for galunisertib (mOS 9.2 vs. 3.6 months;
p
< 0.01). Mechanistically, tumor-derived CCL3 activates Tgfβ signaling in macrophages, inducing their M2 phenotype and Lif secretion, sustaining a mesenchymal/basal-like ecotype. TGFβ inhibition redirects macrophage polarization to M1, reducing Lif and shifting PDAC cells to a more epithelial/classical phenotype, improving gemcitabine sensitivity. This study supports exploring TGFβ-targeting agents in PDAC with a mesenchymal/basal-like ecotype driven by high CCL3 levels.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>39478186</pmid><doi>10.1038/s41698-024-00742-3</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0002-4031-7585</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 631/67/1059/602 692/4028/67/1504/1713 692/53/2423 Biomarkers Cancer Research Cancer therapies Chemokines Gene Therapy Human Genetics Internal Medicine Medical prognosis Medicine Medicine & Public Health Metastasis Oncology Pancreatic cancer Signal transduction Tumors |
| title | CCL3 predicts exceptional response to TGFβ inhibition in basal-like pancreatic cancer enriched in LIF-producing macrophages |
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