An antibody-drug conjugate targeting soluble and membrane-bound TGFα is effective against pancreatic tumors
Abstract Background Pancreatic cancer is one of the most difficult to treat neoplasias. Because of that, the prognosis of the disease is dismal, and identification of novel therapeutic approaches is needed. This study investigates the role of transforming growth factor-alpha (TGFα) in pancreatic can...
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| Format: | Article |
| Language: | English |
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BMC
2025-05-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Online Access: | https://doi.org/10.1186/s13046-025-03421-8 |
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| author | Inés Romero-Pérez Juan Carlos Montero Mónica Redondo-Puente María del Carmen Gómez-García Mireia Morell-Ginestà Gabriel Capellá Atanasio Pandiella |
| author_facet | Inés Romero-Pérez Juan Carlos Montero Mónica Redondo-Puente María del Carmen Gómez-García Mireia Morell-Ginestà Gabriel Capellá Atanasio Pandiella |
| author_sort | Inés Romero-Pérez |
| collection | DOAJ |
| description | Abstract Background Pancreatic cancer is one of the most difficult to treat neoplasias. Because of that, the prognosis of the disease is dismal, and identification of novel therapeutic approaches is needed. This study investigates the role of transforming growth factor-alpha (TGFα) in pancreatic cancer and its potential as a therapeutic target. Methods Using in silico platforms, it was confirmed that TGFA, the gene encoding TGFα, is significantly overexpressed in pancreatic adenocarcinomas relative to normal pancreatic tissues. In patient-derived xenografts as well as in pancreatic cancer cell lines, multiple molecular forms of TGFα were identified, including the transmembrane TGFα precursor (proTGFα) and the soluble 6 kDa mature form. Functional assays using RNA interference and CRISPR/Cas9 demonstrated that TGFA knockdown significantly impaired cell proliferation, reinforcing the critical role of TGFα in driving tumor growth. The therapeutic potential of targeting TGFα was evaluated through the development of two monoclonal antibodies (5F1 and 16B10) specific for TGFα. Results These antibodies effectively bound to proTGFα-expressing cells, with minimal off-target effects in TGFA-knockout cell lines. When conjugated to cytotoxic agents such as MMAF, the resulting antibody-drug conjugates (ADCs) exhibited potent antiproliferative activity, significantly reducing the viability of TGFα-expressing pancreatic cancer cells. Mechanistic studies revealed that MMAF-loaded ADCs induced G2/M cell cycle arrest, with markers of mitotic disruption evident in treated cells. In vivo, the TGFα-targeting ADCs elicited substantial tumor regression in murine models of pancreatic cancer, whereas the unconjugated antibodies merely stabilized tumor growth. Conclusions These findings highlight TGFα as a promising therapeutic target in pancreatic cancer, supporting further preclinical and clinical development of TGFα-directed ADCs. |
| format | Article |
| id | doaj-art-5c908590567d4fcdb2e55a95de5599e1 |
| institution | Kabale University |
| issn | 1756-9966 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-5c908590567d4fcdb2e55a95de5599e12025-08-20T03:54:11ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662025-05-0144111610.1186/s13046-025-03421-8An antibody-drug conjugate targeting soluble and membrane-bound TGFα is effective against pancreatic tumorsInés Romero-Pérez0Juan Carlos Montero1Mónica Redondo-Puente2María del Carmen Gómez-García3Mireia Morell-Ginestà4Gabriel Capellá5Atanasio Pandiella6Instituto de Biología Molecular y Celular del Cáncer- CSIC and CIBERONCInstituto de Biología Molecular y Celular del Cáncer- CSIC and CIBERONCInstituto de Biología Molecular y Celular del Cáncer- CSIC and CIBERONCInstituto de Biología Molecular y Celular del Cáncer- CSIC and CIBERONCHereditary Cancer Program, Catalan Institute of Oncology, Institut d’Investigació Biomèdica de Bellvitge- IDIBELL-ONCOBELL, L’Hospitalet de LlobregatHereditary Cancer Program, Catalan Institute of Oncology, Institut d’Investigació Biomèdica de Bellvitge- IDIBELL-ONCOBELL, L’Hospitalet de LlobregatInstituto de Biología Molecular y Celular del Cáncer- CSIC and CIBERONCAbstract Background Pancreatic cancer is one of the most difficult to treat neoplasias. Because of that, the prognosis of the disease is dismal, and identification of novel therapeutic approaches is needed. This study investigates the role of transforming growth factor-alpha (TGFα) in pancreatic cancer and its potential as a therapeutic target. Methods Using in silico platforms, it was confirmed that TGFA, the gene encoding TGFα, is significantly overexpressed in pancreatic adenocarcinomas relative to normal pancreatic tissues. In patient-derived xenografts as well as in pancreatic cancer cell lines, multiple molecular forms of TGFα were identified, including the transmembrane TGFα precursor (proTGFα) and the soluble 6 kDa mature form. Functional assays using RNA interference and CRISPR/Cas9 demonstrated that TGFA knockdown significantly impaired cell proliferation, reinforcing the critical role of TGFα in driving tumor growth. The therapeutic potential of targeting TGFα was evaluated through the development of two monoclonal antibodies (5F1 and 16B10) specific for TGFα. Results These antibodies effectively bound to proTGFα-expressing cells, with minimal off-target effects in TGFA-knockout cell lines. When conjugated to cytotoxic agents such as MMAF, the resulting antibody-drug conjugates (ADCs) exhibited potent antiproliferative activity, significantly reducing the viability of TGFα-expressing pancreatic cancer cells. Mechanistic studies revealed that MMAF-loaded ADCs induced G2/M cell cycle arrest, with markers of mitotic disruption evident in treated cells. In vivo, the TGFα-targeting ADCs elicited substantial tumor regression in murine models of pancreatic cancer, whereas the unconjugated antibodies merely stabilized tumor growth. Conclusions These findings highlight TGFα as a promising therapeutic target in pancreatic cancer, supporting further preclinical and clinical development of TGFα-directed ADCs.https://doi.org/10.1186/s13046-025-03421-8 |
| spellingShingle | Inés Romero-Pérez Juan Carlos Montero Mónica Redondo-Puente María del Carmen Gómez-García Mireia Morell-Ginestà Gabriel Capellá Atanasio Pandiella An antibody-drug conjugate targeting soluble and membrane-bound TGFα is effective against pancreatic tumors Journal of Experimental & Clinical Cancer Research |
| title | An antibody-drug conjugate targeting soluble and membrane-bound TGFα is effective against pancreatic tumors |
| title_full | An antibody-drug conjugate targeting soluble and membrane-bound TGFα is effective against pancreatic tumors |
| title_fullStr | An antibody-drug conjugate targeting soluble and membrane-bound TGFα is effective against pancreatic tumors |
| title_full_unstemmed | An antibody-drug conjugate targeting soluble and membrane-bound TGFα is effective against pancreatic tumors |
| title_short | An antibody-drug conjugate targeting soluble and membrane-bound TGFα is effective against pancreatic tumors |
| title_sort | antibody drug conjugate targeting soluble and membrane bound tgfα is effective against pancreatic tumors |
| url | https://doi.org/10.1186/s13046-025-03421-8 |
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