{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T02:13:19Z","timestamp":1791339199021,"version":"4.3.1"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,6,16]],"date-time":"2023-06-16T00:00:00Z","timestamp":1686873600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000182","name":"Medical Research and Materiel Command","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000182","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Metastatic disease lacks effective treatments and remains the primary cause of mortality from epithelial cancers, especially breast cancer. The metastatic cascade involves cancer cell migration and invasion and modulation of the tumor microenvironment (TME). A viable anti-metastasis strategy is to simultaneously target the migration of cancer cells and the tumor-infiltrating immunosuppressive inflammatory cells such as activated macrophages, neutrophils, and myeloid-derived suppressor cells (MDSC). The Rho GTPases Rac and Cdc42 are ideal molecular targets that regulate both cancer cell and immune cell migration, as well as their crosstalk signaling at the TME. Therefore, we tested the hypothesis that Rac and Cdc42 inhibitors target immunosuppressive immune cells, in addition to cancer cells. Our published data demonstrate that the Vav\/Rac inhibitor EHop-016 and the Rac\/Cdc42 guanine nucleotide association inhibitor MBQ-167 reduce mammary tumor growth and prevent breast cancer metastasis from pre-clinical mouse models without toxic effects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The potential of Rac\/Cdc42 inhibitors EHop-016 and MBQ-167 to target macrophages was tested in human and mouse macrophage cell lines via activity assays, MTT assays, wound healing, ELISA assays, and phagocytosis assays. Immunofluorescence, immunohistochemistry, and flow cytometry were used to identify myeloid cell subsets from tumors and spleens of mice following EHop-016 or MBQ-167 treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>EHop-016 and MBQ-167 inhibited Rac and Cdc42 activation, actin cytoskeletal extensions, migration, and phagocytosis without affecting macrophage cell viability. Rac\/Cdc42 inhibitors also reduced tumor- infiltrating macrophages and neutrophils in tumors of mice treated with EHop-016, and macrophages and MDSCs from spleens and tumors of mice with breast cancer, including activated macrophages and monocytes, following MBQ-167 treatment. Mice with breast tumors treated with EHop-016 significantly decreased the proinflammatory cytokine Interleukin-6 (IL-6) from plasma and the TME. This was confirmed from splenocytes treated with lipopolysaccharide (LPS) where EHop-016 or MBQ-167 reduced IL-6 secretion in response to LPS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Rac\/Cdc42 inhibition induces an antitumor environment via inhibition of both metastatic cancer cells and immunosuppressive myeloid cells in the TME.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2023.1152458","type":"journal-article","created":{"date-parts":[[2023,6,16]],"date-time":"2023-06-16T06:25:31Z","timestamp":1686896731000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Rac and Cdc42 inhibitors reduce macrophage function in breast cancer preclinical models"],"prefix":"10.3389","volume":"13","author":[{"given":"Anamaris","family":"Torres-Sanchez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Rivera-Robles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linette","family":"Castillo-Pichardo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magaly","family":"Mart\u00ednez-Ferrer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie M.","family":"Dorta-Estremera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suranganie","family":"Dharmawardhane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,6,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-19-0458\/661418\/P\/","article-title":"Defining the hallmarks of metastasis","volume":"79","author":"Welch","year":"2019","journal-title":"Cancer Res"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/J.EJCB.2020.151098","article-title":"The role of the tumor microenvironment in tumor cell intravasation and dissemination","volume":"99","author":"Borriello","year":"2020","journal-title":"Eur J Cell Biol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1146\/ANNUREV.CELLBIO.21.122303.120306","article-title":"The great escape: when cancer cells hijack the genes for chemotaxis and motility","volume":"21","author":"Condeelis","year":"2005","journal-title":"Annu Rev Cell Dev Biol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"02","DOI":"10.3390\/CELLS9102167","article-title":"Rho GTPases: big players in breast cancer initiation, metastasis and therapeutic responses","volume":"9","author":"Humphries","year":"2020","journal-title":"Cells"},{"key":"B5","doi-asserted-by":"publisher","first-page":"3101","DOI":"10.1158\/0008-5472.CAN-18-0619","article-title":"Targeting rac and Cdc42 GTPases in cancer","volume":"78","author":"del Mar Maldonado","year":"2018","journal-title":"Cancer Res"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1042\/BST20170519","article-title":"The role of rac in tumor susceptibility and disease progression: from biochemistry to the clinic","volume":"46","author":"Casado-Medrano","year":"2018","journal-title":"Biochem Soc Trans"},{"key":"B7","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1038\/NRI3789","article-title":"Immune cell promotion of metastasis","volume":"15","author":"Kitamura","year":"2015","journal-title":"Nat Rev Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/J.CCR.2013.02.013","article-title":"Macrophage regulation of tumor responses to anticancer therapies","volume":"23","author":"de Palma","year":"2013","journal-title":"Cancer Cell"},{"key":"B9","doi-asserted-by":"publisher","first-page":"02","DOI":"10.1371\/JOURNAL.PONE.0050946","article-title":"Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature","volume":"7","author":"Zhang","year":"2012","journal-title":"PLoS One"},{"key":"B10","doi-asserted-by":"publisher","first-page":"02","DOI":"10.1093\/JNCI\/DJU124","article-title":"Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis","volume":"106","author":"Templeton","year":"2014","journal-title":"J Natl Cancer Inst"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-17-2158","article-title":"Inflammatory breast cancer promotes development of M2 tumor-associated macrophages and cancer mesenchymal cells through a complex chemokine network","volume":"79","author":"Valeta-Magara","year":"2019","journal-title":"Cancer Res"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/J.TRECAN.2018.03.011","article-title":"Distant relations: macrophage functions in the metastatic niche","volume":"4","author":"Doak","year":"2018","journal-title":"Trends Cancer"},{"key":"B13","doi-asserted-by":"publisher","first-page":"38","DOI":"10.4048\/JBC.2019.22.E5","article-title":"Tumor-associated macrophages as potential prognostic biomarkers of invasive breast cancer","volume":"22","author":"Jeong","year":"2019","journal-title":"J Breast Cancer"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/J.CCR.2009.06.017","article-title":"Polarization of tumor-associated neutrophil phenotype by TGF-beta: \u201cN1\u201d versus \u201cN2\u201d TAN","volume":"16","author":"Fridlender","year":"2009","journal-title":"Cancer Cell"},{"key":"B15","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1158\/2159-8274.CD-10-0028","article-title":"Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy","volume":"1","author":"DeNardo","year":"2011","journal-title":"Cancer Discovery"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/S12929-019-0568-Z","article-title":"Tumor-associated macrophages: an accomplice in solid tumor progression","volume":"26","author":"Chen","year":"2019","journal-title":"J Biomed Sci"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/S12885-015-1546-9\/FIGURES\/10","article-title":"M1 and M2 macrophages derived from THP-1 cells differentially modulate the response of cancer cells to etoposide","volume":"15","author":"Genin","year":"2015","journal-title":"BMC Cancer"},{"key":"B18","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1111\/NYAS.14377","article-title":"Macrophage targeting in cancer","volume":"1499","author":"Lopez-Yrigoyen","year":"2021","journal-title":"Ann N Y Acad Sci"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2008.65","article-title":"MyD88-independent activation of a novel actin-Cdc42\/Rac pathway is required for toll-like receptor-stimulated phagocytosis","volume":"18","author":"Kong","year":"2008","journal-title":"Cell Res"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1203458","article-title":"IL-4 regulation of IL-6 production involves Rac\/Cdc42- and p38 MAPK-dependent pathways in keratinocytes","volume":"19","author":"Wery-Zennaro","year":"2000","journal-title":"Oncogene"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1111\/BPH.12658","article-title":"Targeting rho-GTPases in immune cell migration and inflammation","volume":"171","author":"Biro","year":"2014","journal-title":"Br J Pharmacol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/J.CELL.2006.01.007","article-title":"Macrophages: obligate partners for tumor cell migration, invasion, and metastasis","volume":"124","author":"Condeelis","year":"2006","journal-title":"Cell"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1242\/JCS.183129","article-title":"Signatures of breast cancer metastasis at a glance","volume":"129","author":"Karagiannis","year":"2016","journal-title":"J Cell Sci"},{"key":"B24","doi-asserted-by":"publisher","first-page":"02","DOI":"10.1101\/CSHPERSPECT.A038026","article-title":"Myeloid cells in metastasis","volume":"10","author":"Swierczak","year":"2020","journal-title":"Cold Spring Harb Perspect Med"},{"key":"B25","doi-asserted-by":"publisher","first-page":"13228","DOI":"10.1074\/JBC.M111.334524","article-title":"Characterization of EHop-016, novel small molecule inhibitor of rac GTPase","volume":"287","author":"Montalvo-Ortiz","year":"2012","journal-title":"J Biol Chem"},{"key":"B26","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1158\/1535-7163.MCT-16-0442","article-title":"Characterization of a dual Rac\/Cdc42 inhibitor MBQ-167 in metastatic cancer","volume":"16","author":"Humphries-Bickley","year":"2017","journal-title":"Mol Cancer Ther"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-21-0348","article-title":"Efficacy of rac and Cdc42 inhibitor MBQ-167 in triple-negative breast cancer","volume":"20","author":"Cruz-Collazo","year":"2021","journal-title":"Mol Cancer Ther"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1021\/ACSOMEGA.9B01641","article-title":"Pharmacokinetics of the Rac\/Cdc42 inhibitor MBQ-167 in mice by supercritical fluid chromatography-tandem mass spectrometry","volume":"4","author":"del Mar Maldonado","year":"2019","journal-title":"ACS Omega"},{"key":"B29","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1016\/J.TRANON.2014.07.004","article-title":"The rac inhibitor EHop-016 inhibits mammary tumor growth and metastasis in a nude mouse model","volume":"7","author":"Castillo-Pichardo","year":"2014","journal-title":"Transl Oncol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1158\/2767-9764.CRC-22-0303","article-title":"Characterization of novel derivatives of MBQ-167, an inhibitor of the GTP-binding proteins Rac\/Cdc42","volume":"2","author":"Medina","year":"2022","journal-title":"Cancer Res Commun"},{"key":"B31","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1016\/J.IJROBP.2018.06.404","article-title":"Kinetics of intratumoral immune cell activation during chemoradiation for cervical cancer","volume":"102","author":"Dorta-Estremera","year":"2018","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1172\/JCI67509","article-title":"Pak and rac GTPases promote oncogenic KIT-induced neoplasms","volume":"123","author":"Martin","year":"2013","journal-title":"J Clin Invest"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80019-9","article-title":"Deficiency of the hematopoietic cell-specific rho family GTPase Rac2 is characterized by abnormalities in neutrophil function and host defense","volume":"10","author":"Roberts","year":"1999","journal-title":"Immunity"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-800255-1.00007-7","article-title":"Role of p-21-activated kinases in cancer progression","volume":"309","author":"King","year":"2014","journal-title":"Int Rev Cell Mol Biol"},{"key":"B35","doi-asserted-by":"publisher","first-page":"89","DOI":"10.4161\/21541248.2014.989785","article-title":"Regulation of phagocytosis by rho GTPases","volume":"6","author":"Mao","year":"2015","journal-title":"Small GTPases"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1571","DOI":"10.4161\/CC.10.10.15612","article-title":"The diverse roles of rac signaling in tumorigenesis","volume":"10","author":"Mack","year":"2011","journal-title":"Cell Cycle"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1042\/BST20050891","article-title":"Rho GTPases and the control of cell behaviour","volume":"33","author":"Hall","year":"2005","journal-title":"Biochem Soc Trans"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-17-1456","article-title":"The rac GTPase in cancer: from old concepts to new paradigms","volume":"77","author":"Kazanietz","year":"2017","journal-title":"Cancer Res"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1097\/00062752-199704010-00003","article-title":"Rho GTPases and leukocyte cytoskeletal regulation","volume":"4","author":"Dharmawardhane","year":"1997","journal-title":"Curr Opin Hematol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1097\/00062752-200301000-00003","article-title":"Regulation of neutrophil function by rac GTPases","volume":"10","author":"Dinauer","year":"2003","journal-title":"Curr Opin Hematol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1016\/J.MOLCEL.2017.01.021","article-title":"The TRAIL-induced cancer secretome promotes a tumor-supportive immune microenvironment via CCR2","volume":"65","author":"Hartwig","year":"2017","journal-title":"Mol Cell"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.21037\/TAU-20-943","article-title":"Myeloid-derived suppressor cell (MDSC) key genes analysis in rat anti-CD28-induced immune tolerance kidney transplantation","volume":"10","author":"Yang","year":"2021","journal-title":"Transl Androl Urol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1371\/JOURNAL.PONE.0042563","article-title":"Rho GTPase expression in human myeloid cells","volume":"7","author":"van Helden","year":"2012","journal-title":"PLoS One"},{"key":"B44","doi-asserted-by":"publisher","first-page":"88","DOI":"10.5551\/JAT.11.88","article-title":"A comparison of differences in the gene expression profiles of phorbol 12-myristate 13-acetate differentiated THP-1 cells and human monocyte-derived macrophage","volume":"11","author":"Kohro","year":"2004","journal-title":"J Atheroscler Thromb"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.3389\/FIMMU.2021.679458\/BIBTEX","article-title":"Comparative proteomic analysis reveals varying impact on immune responses in phorbol 12-Myristate-13-Acetate-Mediated THP-1 monocyte-to-Macrophage differentiation","volume":"12","author":"Pinto","year":"2021","journal-title":"Front Immunol"},{"key":"B46","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/S12885-021-08366-7\/FIGURES\/6","article-title":"Rac inhibition as a novel therapeutic strategy for EGFR\/HER2 targeted therapy resistant breast cancer","volume":"21","author":"Borrero-Garc\u00eda","year":"2021","journal-title":"BMC Cancer"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1080\/21541248.2018.1495008","article-title":"Targeting Cdc42 with the anticancer compound MBQ-167 inhibits cell polarity and growth in the budding yeast s. cerevisiae","volume":"11","author":"Rivera-Robles","year":"2020","journal-title":"Small GTPases"},{"key":"B48","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/PHARMACEUTICS12100975","article-title":"Physiologically-based Pharmacokinetic\/Pharmacodynamic model of MBQ-167 to predict tumor growth inhibition in mice","volume":"12","author":"Reig-L\u00f3pez","year":"2020","journal-title":"Pharmaceutics"},{"key":"B49","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/J.JCHROMB.2014.12.021","article-title":"Pharmacokinetics of rac inhibitor EHop-016 in mice by ultra-performance liquid chromatography tandem mass spectrometry","author":"Humphries-Bickley","year":"2015","journal-title":"J Chromatogr B Analyt Technol BioMed Life Sci"},{"key":"B50","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1155\/2016\/6031486","article-title":"Monocyte differentiation towards protumor activity does not correlate with M1 or M2 phenotypes","volume":"2016","author":"Chimal-Ram\u00edrez","year":"2016","journal-title":"J Immunol Res"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.3389\/FIMMU.2020.583084\/BIBTEX","article-title":"Tumor-associated macrophages in tumor immunity","volume":"11","author":"Pan","year":"2020","journal-title":"Front Immunol"},{"key":"B52","doi-asserted-by":"publisher","first-page":"12","DOI":"10.3390\/BIOMEDICINES9040374","article-title":"Tumor-associated macrophages-implications for molecular oncology and imaging","volume":"9","author":"Kimm","year":"2021","journal-title":"Biomedicines"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.4049\/JIMMUNOL.0802740","article-title":"Myeloid-derived suppressor cells: linking inflammation and cancer","volume":"182","author":"Ostrand-Rosenberg","year":"2009","journal-title":"J Immunol"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-17-2268","article-title":"IL-6 mediates cross-talk between tumor cells and activated fibroblasts in the tumor microenvironment","volume":"78","author":"Karakasheva","year":"2018","journal-title":"Cancer Res"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1172\/JCI57099","article-title":"Breast cancer stem cells, cytokine networks, and the tumor microenvironment","volume":"121","author":"Korkaya","year":"2011","journal-title":"J Clin Invest"},{"key":"B56","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/J.SMIM.2014.01.007","article-title":"The IL-6 feed-forward loop: a driver of tumorigenesis","volume":"26","author":"Chang","year":"2014","journal-title":"Semin Immunol"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.3389\/FONC.2022.866014","article-title":"IL-6\/JAK\/STAT3 signaling in breast cancer metastasis: biology and treatment","volume":"12","author":"Manore","year":"2022","journal-title":"Front Oncol"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1016\/J.IMLET.2018.02.009","article-title":"Regulation of immunophenotype modulation of monocytes-macrophages from M1 into M2 by prostate cancer cell-culture supernatant via transcription factor STAT3","volume":"196","author":"Sol\u00eds-Mart\u00ednez","year":"2018","journal-title":"Immunol Lett"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1177\/1759720X10378372","article-title":"The role of interleukin 6 in the pathophysiology of rheumatoid arthritis","volume":"2","author":"Srirangan","year":"2010","journal-title":"Ther Adv Musculoskelet Dis"},{"key":"B60","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1016\/J.CCELL.2022.04.004","article-title":"Interleukin-6 blockade abrogates immunotherapy toxicity and promotes tumor immunity","volume":"40","author":"Hailemichael","year":"2022","journal-title":"Cancer Cell"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1093\/INTIMM\/DXAA078","article-title":"IL-6 in inflammation, autoimmunity and cancer","volume":"33","author":"Hirano","year":"2021","journal-title":"Int Immunol"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2023.1152458\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,16]],"date-time":"2023-06-16T06:25:34Z","timestamp":1686896734000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2023.1152458\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,16]]},"references-count":61,"alternative-id":["10.3389\/fonc.2023.1152458"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2023.1152458","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,16]]},"article-number":"1152458"}}