{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T04:36:34Z","timestamp":1769661394666,"version":"3.49.0"},"reference-count":101,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T00:00:00Z","timestamp":1769558400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European EuroTrans-Bio Grant","award":["ETB-2011-03"],"award-info":[{"award-number":["ETB-2011-03"]}]},{"name":"National Plan for Complementary Investments to the NRRP","award":["PNC0000001"],"award-info":[{"award-number":["PNC0000001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: The progression and dissemination of CRC are heavily influenced by a subpopulation of tumor cells known as CSCs. This study aimed to identify novel protein membrane antigens expressed by colorectal CSCs and the consequent development of targeted therapies based on monoclonal antibodies directed against the identified antigens. Methods: Integrated bioinformatics analyses were conducted using proprietary CSC gene expression profiles and public colon gene expression databases, leading to the identification of five plasma membrane proteins enriched in CSCs. Genetic immunization in rats was employed to generate monoclonal antibodies (mAbs) targeting these antigens. FGFR4 was prioritized due to its overexpression in colorectal tumors. Its function was characterized in vitro and in vivo through assays evaluating proliferation, colony formation, migration, and tumorigenicity. The anti-FGFR4 antibody 3B6 was selected based on its affinity and ability to inhibit FGFR4 signaling in CSCs. Its therapeutic potential was further assessed in xenograft models, and alterations in downstream signaling were analyzed via Western blot. Results: FGFR4 emerged as a key regulator of CRC CSC proliferation, migration, and tumorigenic capacity. The 3B6 antibody, a high-affinity FGFR4 binder, demonstrated robust in vitro inhibition of CSC features and significant antitumor effects in patient-derived xenograft models. Western blot analysis confirmed the modulation of FGFR4-driven signaling pathways, particularly those involved in epithelial\u2013mesenchymal transition (EMT). Conclusions: This study successfully identified several CSC-selective membrane antigens that can become therapeutic targets in CRC. Among them, we focused on FGFR4 as a promising target and developed the anti-FGFR4 3B6 monoclonal antibody which offers potential for both diagnostic and therapeutic applications.<\/jats:p>","DOI":"10.3390\/cancers18030418","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T15:56:12Z","timestamp":1769615772000},"page":"418","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting Colorectal Cancer Stem Cells Through Inhibition of the Fibroblast Growth Factor Receptor 4 Pathway with a Novel Antibody"],"prefix":"10.3390","volume":"18","author":[{"given":"Gessica","family":"Filocamo","sequence":"first","affiliation":[{"name":"Exiris s.r.l., Tecnopolo Castel Romano, 00128 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1157-4694","authenticated-orcid":false,"given":"Mariachiara","family":"Buccarelli","sequence":"additional","affiliation":[{"name":"Department of Oncology and Molecular Medicine, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Armin","family":"Lahm","sequence":"additional","affiliation":[{"name":"Bioinformatics Project Support, 00153 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mirko","family":"Brunetti","sequence":"additional","affiliation":[{"name":"Exiris s.r.l., Tecnopolo Castel Romano, 00128 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chantal","family":"Paolini","sequence":"additional","affiliation":[{"name":"IRBM S.p.A., 00071 Pomezia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriele","family":"De Luca","sequence":"additional","affiliation":[{"name":"Department of Oncology and Molecular Medicine, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0262-842X","authenticated-orcid":false,"given":"Michele","family":"Signore","sequence":"additional","affiliation":[{"name":"RPPA Unit, Proteomics Area, Core Facilities, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giorgia","family":"Castellani","sequence":"additional","affiliation":[{"name":"Department of Oncology and Molecular Medicine, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8888-7501","authenticated-orcid":false,"given":"Alessandra","family":"Boe","sequence":"additional","affiliation":[{"name":"Cytometry Unit, Core Facilities, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Romina","family":"Alfonsi","sequence":"additional","affiliation":[{"name":"National Centre for Control and Evaluation of Medicines, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mauro","family":"Biffoni","sequence":"additional","affiliation":[{"name":"Department of Oncology and Molecular Medicine, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2255-0583","authenticated-orcid":false,"given":"Ruggero","family":"De Maria","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina e Chirurgia Traslazionale, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"},{"name":"Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucia","family":"Ricci-Vitiani","sequence":"additional","affiliation":[{"name":"Department of Oncology and Molecular Medicine, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Steink\u00fchler","sequence":"additional","affiliation":[{"name":"Exiris s.r.l., Tecnopolo Castel Romano, 00128 Rome, Italy"},{"name":"Research and Development, Italfarmaco Group, 20092 Cinisello Balsamo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0166-9422","authenticated-orcid":false,"given":"Paola","family":"Gallinari","sequence":"additional","affiliation":[{"name":"Exiris s.r.l., Tecnopolo Castel Romano, 00128 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,28]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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