{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T07:13:53Z","timestamp":1789456433955,"version":"build-2803163510"},"reference-count":34,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Oncology"],"abstract":"<jats:p>\n                    FAK\/PTK2 is widely considered a therapeutic target in cancer, although its role in tumorigenesis remains context\u2010dependent. Here, we investigated whether different degrees of FAK suppression produce distinct effects on tumor progression and whether macrophage p110\u03b4 PI3K inactivation can counteract adverse effects associated with incomplete FAK inhibition. Using MDA\u2010MB\u2010231 breast cancer cell clones stably transfected with FAK\/PTK2\u2010shRNA, we found that strong FAK suppression impaired tumor growth, whereas moderate FAK silencing promoted rapid tumor expansion in female and male mice. Intratumoral FAK\/PTK2\u2010siRNA inducing moderate FAK suppression similarly accelerated breast tumor growth, increased proliferation, reduced apoptosis, and increased circulating tumor cells. Transfer of macrophages expressing genetically inactive p110\u03b4 significantly reduced the tumor burden induced by moderately FAK\u2010silenced breast cancer cells, decreased proliferation, and increased apoptosis. In melanoma tumors, suboptimal pharmacological inhibition of FAK increased tumor burden, whereas combined treatment with a selective p110\u03b4 inhibitor prevented this effect, reduced circulating melanoma cells, suppressed proliferation, and enhanced apoptosis. Since FAK inhibitors may not achieve complete and sustained inhibition of FAK activity\n                    <jats:italic>in vivo<\/jats:italic>\n                    , our findings highlight the possibility that partial FAK suppression may generate adverse biological outcomes and identify macrophage p110\u03b4PI3K as a complementary therapeutic strategy to prevent tumor\u2010promoting consequences arising from incomplete FAK inhibition.\n                  <\/jats:p>","DOI":"10.1002\/1878-0261.70320","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T06:45:17Z","timestamp":1789454717000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Partial\n                    <scp>FAK<\/scp>\n                    suppression promotes tumor growth, an effect reversed by macrophage p110\u03b4\n                    <scp>PI3K<\/scp>\n                    inactivation"],"prefix":"10.1002","author":[{"given":"Lydia","family":"Xenou","sequence":"first","affiliation":[{"name":"Department of Biochemistry, School of Medicine University of Crete  Heraklion Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niki","family":"Tzenaki","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, School of Medicine University of Crete  Heraklion Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Tsapara","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, School of Medicine University of Crete  Heraklion Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Tzardi","sequence":"additional","affiliation":[{"name":"Department of Pathology University Hospital, School of Medicine, University of Crete  Heraklion Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7119-6026","authenticated-orcid":false,"given":"Evangelia A.","family":"Papakonstanti","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, School of Medicine University of Crete  Heraklion Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,14]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"crossref","DOI":"10.3389\/fpubh.2025.1622954","article-title":"Global burden and projections of breast cancer incidence and mortality to 2050: a comprehensive analysis of GLOBOCAN data","volume":"13","author":"Freihat O","year":"2025","journal-title":"Front Public Health"},{"issue":"3","key":"e_1_2_11_3_1","first-page":"209","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung H","year":"2021","journal-title":"CA Cancer J Clin"},{"key":"e_1_2_11_4_1","doi-asserted-by":"crossref","DOI":"10.3389\/fonc.2022.991758","article-title":"Editorial: molecular mechanisms in breast cancer progression and metastasis","volume":"12","author":"Fedele M","year":"2022","journal-title":"Front Oncol"},{"issue":"11","key":"e_1_2_11_5_1","doi-asserted-by":"crossref","DOI":"10.31083\/j.fbl2911392","article-title":"Signal transduction mechanisms of focal adhesions: Src and FAK\u2010mediated cell response","volume":"29","author":"Katoh K","year":"2024","journal-title":"Front Biosci (Landmark Ed)"},{"issue":"6","key":"e_1_2_11_6_1","doi-asserted-by":"crossref","DOI":"10.3390\/cancers10060196","article-title":"Endogenous control mechanisms of FAK and PYK2 and their relevance to cancer development","volume":"10","author":"Naser R","year":"2018","journal-title":"Cancers (Basel)"},{"issue":"9","key":"e_1_2_11_7_1","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1038\/nrc3792","article-title":"FAK in cancer: mechanistic findings and clinical applications","volume":"14","author":"Sulzmaier FJ","year":"2014","journal-title":"Nat Rev Cancer"},{"issue":"1","key":"e_1_2_11_8_1","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s10555-008-9165-4","article-title":"Signal transduction by focal adhesion kinase in cancer","volume":"28","author":"Zhao J","year":"2009","journal-title":"Cancer Metastasis Rev"},{"issue":"2","key":"e_1_2_11_9_1","doi-asserted-by":"crossref","first-page":"221","DOI":"10.2174\/1566524014666140128110339","article-title":"RhoGEFs in cell motility: novel links between Rgnef and focal adhesion kinase","volume":"14","author":"Miller NL","year":"2014","journal-title":"Curr Mol Med"},{"issue":"5","key":"e_1_2_11_10_1","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1038\/s41568-021-00340-6","article-title":"Targeting FAK in anticancer combination therapies","volume":"21","author":"Dawson JC","year":"2021","journal-title":"Nat Rev Cancer"},{"issue":"7","key":"e_1_2_11_11_1","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1242\/jcs.045112","article-title":"Cellular functions of FAK kinases: insight into molecular mechanisms and novel functions","volume":"123","author":"Schaller MD","year":"2010","journal-title":"J Cell Sci"},{"issue":"1","key":"e_1_2_11_12_1","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1007\/s11033-025-11284-7","article-title":"The integrin\u2010matrix\u2010FAK\u2010EMT axis in Anoikis resistance: a critical network in tumor progression and therapy","volume":"53","author":"Alabas E","year":"2025","journal-title":"Mol Biol Rep"},{"key":"e_1_2_11_13_1","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.1111\/bph.70376","article-title":"Novel drugs approved by the EMA, the FDA and the MHRA in 2025: a year in review","volume":"183","author":"Papapetropoulos A","year":"2026","journal-title":"Br J Pharmacol"},{"key":"e_1_2_11_14_1","doi-asserted-by":"crossref","DOI":"10.3389\/fonc.2025.1724278","article-title":"Context\u2010specific targeting of focal adhesion kinase in brain tumors: lessons from glioblastoma and neurofibromatosis type 2\u2010mutant meningioma","volume":"15","author":"Sagerer A","year":"2025","journal-title":"Front Oncol"},{"issue":"20","key":"e_1_2_11_15_1","doi-asserted-by":"crossref","DOI":"10.3390\/ijms262010108","article-title":"Kinome\u2010wide screening identifies FAK as a novel post\u2010translational regulator of PD\u2010L1 stability and immune evasion in triple\u2010negative breast cancer","volume":"26","author":"Boyd AL","year":"2025","journal-title":"Int J Mol Sci"},{"key":"e_1_2_11_16_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejphar.2023.175694","article-title":"Dual roles of FAK in tumor angiogenesis: a review focused on pericyte FAK","volume":"947","author":"Zhang J","year":"2023","journal-title":"Eur J Pharmacol"},{"issue":"4","key":"e_1_2_11_17_1","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1016\/j.bbrc.2008.07.123","article-title":"Biphasic function of focal adhesion kinase in endothelial tube formation induced by fibril\u2010forming collagens","volume":"374","author":"Nakamura J","year":"2008","journal-title":"Biochem Biophys Res Commun"},{"key":"e_1_2_11_18_1","doi-asserted-by":"crossref","first-page":"2020","DOI":"10.1038\/ncomms3020","article-title":"FAK\u2010heterozygous mice display enhanced tumour angiogenesis","volume":"4","author":"Kostourou V","year":"2013","journal-title":"Nat Commun"},{"issue":"12","key":"e_1_2_11_19_1","doi-asserted-by":"crossref","first-page":"4840","DOI":"10.1096\/fj.15-274589","article-title":"Focal adhesion kinase phosphorylates the phosphatase and tensin homolog deleted on chromosome 10 under the control of p110delta phosphoinositide\u20103 kinase","volume":"29","author":"Tzenaki N","year":"2015","journal-title":"FASEB J"},{"key":"e_1_2_11_20_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.bioorg.2026.109706","article-title":"Rational design of dual ALK inhibitors: scaffolds and strategies to circumvent drug resistance","volume":"174","author":"Yahya TAA","year":"2026","journal-title":"Bioorg Chem"},{"issue":"1","key":"e_1_2_11_21_1","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1007\/s11033-025-10296-7","article-title":"Focal adhesion kinase (FAK): emerging target for drug\u2010resistant malignant tumors","volume":"52","author":"Aakriti J","year":"2025","journal-title":"Mol Biol Rep"},{"issue":"2","key":"e_1_2_11_22_1","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/s12032-025-03161-x","article-title":"Macrophage\u2010cancer cell crosstalk in breast cancer chemotherapy resistance","volume":"43","author":"Guo AI","year":"2025","journal-title":"Med Oncol"},{"issue":"6","key":"e_1_2_11_23_1","doi-asserted-by":"crossref","DOI":"10.1038\/s41419-018-0717-4","article-title":"Pharmacological inactivation of the PI3K p110delta prevents breast tumour progression by targeting cancer cells and macrophages","volume":"9","author":"Goulielmaki E","year":"2018","journal-title":"Cell Death Dis"},{"issue":"1","key":"e_1_2_11_24_1","doi-asserted-by":"crossref","DOI":"10.1038\/s42003-023-05639-8","article-title":"A combined opposite targeting of p110delta PI3K and RhoA abrogates skin cancer","volume":"7","author":"Tzenaki N","year":"2024","journal-title":"Commun Biol"},{"key":"e_1_2_11_25_1","doi-asserted-by":"crossref","DOI":"10.1038\/s41420-026-03073-3","article-title":"IOA\u2010244, a novel p110delta PI3K inhibitor, blocks breast tumour progression on either mono\u2010 or combined\u2010therapy","volume":"12","author":"Goulielmaki E","year":"2026","journal-title":"Cell Death Discov"},{"issue":"3","key":"e_1_2_11_26_1","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1007\/BF00300234","article-title":"Determination of subcutaneous tumor size in athymic (nude) mice","volume":"24","author":"Tomayko MM","year":"1989","journal-title":"Cancer Chemother Pharmacol"},{"issue":"4","key":"e_1_2_11_27_1","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1002\/jso.2930310402","article-title":"Tumor measurement in the nude mouse","volume":"31","author":"Euhus DM","year":"1986","journal-title":"J Surg Oncol"},{"issue":"4","key":"e_1_2_11_28_1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0019309","article-title":"Simultaneous siRNA targeting of Src and downstream signaling molecules inhibit tumor formation and metastasis of a human model breast cancer cell line","volume":"6","author":"Bjorge JD","year":"2011","journal-title":"PLoS One"},{"issue":"3","key":"e_1_2_11_29_1","doi-asserted-by":"crossref","first-page":"1765","DOI":"10.1074\/jbc.M806239200","article-title":"Membrane\u2010type 1 matrix metalloproteinase regulates macrophage\u2010dependent Elastolytic activity and aneurysm formation in vivo","volume":"284","author":"Xiong W","year":"2009","journal-title":"J Biol Chem"},{"key":"e_1_2_11_30_1","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1126\/science.1073560","article-title":"Impaired B and T\u00a0cell antigen receptor signaling in p110\u03b4 PI 3\u2010kinase mutant mice","volume":"297","author":"Okkenhaug K","year":"2002","journal-title":"Science"},{"issue":"1","key":"e_1_2_11_31_1","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1158\/0008-5472.CAN-05-1242","article-title":"Epidermal growth factor receptor overexpression results in increased tumor cell motility in vivo coordinately with enhanced Intravasation and metastasis","volume":"66","author":"Xue C","year":"2006","journal-title":"Cancer Res"},{"issue":"6","key":"e_1_2_11_32_1","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1096\/fj.11-198192","article-title":"High levels of p110delta PI3K expression in solid tumor cells suppress PTEN activity, generating cellular sensitivity to p110delta inhibitors through PTEN activation","volume":"26","author":"Tzenaki N","year":"2012","journal-title":"FASEB J"},{"issue":"20","key":"e_1_2_11_33_1","doi-asserted-by":"crossref","first-page":"14845","DOI":"10.1074\/jbc.M606695200","article-title":"Cellular characterization of a novel focal adhesion kinase inhibitor","volume":"282","author":"Slack\u2010Davis JK","year":"2007","journal-title":"J Biol Chem"},{"issue":"5","key":"e_1_2_11_34_1","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/nrm2882","article-title":"The emerging mechanisms of isoform\u2010specific PI3K signalling","volume":"11","author":"Vanhaesebroeck B","year":"2010","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"7911","key":"e_1_2_11_35_1","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1038\/s41586-022-04685-2","article-title":"Intermittent PI3Kdelta inhibition sustains anti\u2010tumour immunity and curbs irAEs","volume":"605","author":"Eschweiler S","year":"2022","journal-title":"Nature"}],"container-title":["Molecular Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/1878-0261.70320","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/1878-0261.70320","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/1878-0261.70320","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T06:45:22Z","timestamp":1789454722000},"score":1,"resource":{"primary":{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/10.1002\/1878-0261.70320"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,14]]},"references-count":34,"alternative-id":["10.1002\/1878-0261.70320"],"URL":"https:\/\/doi.org\/10.1002\/1878-0261.70320","archive":["Portico"],"relation":{},"ISSN":["1574-7891","1878-0261"],"issn-type":[{"value":"1574-7891","type":"print"},{"value":"1878-0261","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,14]]},"assertion":[{"value":"2026-06-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-16","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"1878-0261.70320"}}