{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T18:39:09Z","timestamp":1790966349060,"version":"4.1.0"},"reference-count":40,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,2,23]],"date-time":"2024-02-23T00:00:00Z","timestamp":1708646400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"2021 Catalyst Award, Dr. Ralph and Marian Falk Medical Research Trust","award":["5T35DK060444-20"],"award-info":[{"award-number":["5T35DK060444-20"]}]},{"name":"2023 Pilot Project Award Program, University of Cincinnati Cancer Center","award":["5T35DK060444-20"],"award-info":[{"award-number":["5T35DK060444-20"]}]},{"name":"2023 Fellowship in the Medical Student Summer Research Program (MSSRP)","award":["5T35DK060444-20"],"award-info":[{"award-number":["5T35DK060444-20"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alternatively spliced tissue factor (asTF) promotes the progression of pancreatic ductal adenocarcinoma (PDAC) by activating \u03b21-integrins on PDAC cell surfaces. hRabMab1, a first-in-class humanized inhibitory anti-asTF antibody we recently developed, can suppress PDAC primary tumor growth as a single agent. Whether hRabMab1 has the potential to suppress metastases in PDAC is unknown. Following in vivo screening of three asTF-proficient human PDAC cell lines, we chose to make use of KRAS G12V-mutant human PDAC cell line PaCa-44, which yields aggressive primary orthotopic tumors with spontaneous spread to PDAC-relevant anatomical sites, along with concomitant severe leukocytosis. The experimental design featured orthotopic tumors formed by luciferase labeled PaCa-44 cells; administration of hRabMab1 alone or in combination with gemcitabine\/paclitaxel (gem\/PTX); and the assessment of the treatment outcomes on the primary tumor tissue as well as systemic spread. When administered alone, hRabMab1 exhibited poor penetration of tumor tissue; however, hRabMab1 was abundant in tumor tissue when co-administered with gem\/PTX, which resulted in a significant decrease in tumor cell proliferation; leukocyte infiltration; and neovascularization. Gem\/PTX alone reduced primary tumor volume, but not metastatic spread; only the combination of hRabMab1 and gem\/PTX significantly reduced metastatic spread. RNA-seq analysis of primary tumors showed that the addition of hRabMab1 to gem\/PTX enhanced the downregulation of tubulin binding and microtubule motor activity. In the liver, hRabMab1 reduced liver metastasis as a single agent. Only the combination of hRabMab1 and gem\/PTX eliminated tumor cell-induced leukocytosis. We here demonstrate for the first time that hRabMab1 may help suppress metastasis in PDAC. hRabMab1\u2019s ability to improve the efficacy of chemotherapy is significant and warrants further investigation.<\/jats:p>","DOI":"10.3390\/ijms25052580","type":"journal-article","created":{"date-parts":[[2024,2,23]],"date-time":"2024-02-23T04:31:23Z","timestamp":1708662683000},"page":"2580","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["First-in-Class Humanized Antibody against Alternatively Spliced Tissue Factor Augments Anti-Metastatic Efficacy of Chemotherapy in a Preclinical Model of Pancreatic Ductal Adenocarcinoma"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4694-9970","authenticated-orcid":false,"given":"Clayton S.","family":"Lewis","sequence":"first","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Internal Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Backman","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Internal Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabahat","family":"Ahsan","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Internal Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7809-5546","authenticated-orcid":false,"given":"Ashley","family":"Cliff","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthi","family":"Hariharan","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jen Jen","family":"Yeh","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"},{"name":"Departments of Surgery and Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7371-4085","authenticated-orcid":false,"given":"Xiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Environmental Genetics and Molecular Toxicology, Department of Environmental and Public Health Sciences, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changchun","family":"Xie","sequence":"additional","affiliation":[{"name":"Division of Biostatistics and Bioinformatics, Department of Environmental and Public Health Sciences, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davendra P. S.","family":"Sohal","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Internal Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4968-1129","authenticated-orcid":false,"given":"Vladimir Y.","family":"Bogdanov","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Internal Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1182\/blood-2017-03-743211","article-title":"Cancer-associated pathways and biomarkers of venous thrombosis","volume":"130","author":"Hisada","year":"2017","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5543","DOI":"10.1182\/blood-2012-01-402156","article-title":"Tumor-derived tissue factor activates coagulation and enhances thrombosis in a mouse xenograft model of human pancreatic cancer","volume":"119","author":"Wang","year":"2012","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1182\/blood-2011-06-317685","article-title":"The relationship between tissue factor and cancer progression: Insights from bench and bedside","volume":"119","author":"Osanto","year":"2012","journal-title":"Blood"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"842","DOI":"10.3109\/0284186X.2013.705890","article-title":"Early growth response gene-1 and hypoxia-inducible factor-1\u03b1 affect tumor metastasis via regulation of tissue factor","volume":"52","author":"Sun","year":"2013","journal-title":"Acta Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1055\/s-2008-1079257","article-title":"Diverse roles of tissue factor-expressing cell subsets in tumor progression","volume":"34","author":"Milsom","year":"2008","journal-title":"Semin. 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