FOXO transcriptional activity is associated with response to chemoradiation in EAC
Abstract In this study we aimed to investigate signaling pathways that drive therapy resistance in esophageal adenocarcinoma (EAC). Paraffin-embedded material was analyzed in two patient cohorts: (i) 236 EAC patients with a primary tumor biopsy and corresponding post neoadjuvant chemoradiotherapy (n...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-04-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-022-03376-w |
| _version_ | 1811289700858593280 |
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| author | A. Creemers A. P. van der Zalm A. van de Stolpe L. Holtzer M. Stoffels G. K. J. Hooijer E. A. Ebbing H. van Ooijen A. G. C. van Brussel E. M. G. Aussems-Custers M. I. van Berge Henegouwen M. C. C. M. Hulshof J. J. G. H. M. Bergman S. L. Meijer M. F. Bijlsma H. W. M. van Laarhoven |
| author_facet | A. Creemers A. P. van der Zalm A. van de Stolpe L. Holtzer M. Stoffels G. K. J. Hooijer E. A. Ebbing H. van Ooijen A. G. C. van Brussel E. M. G. Aussems-Custers M. I. van Berge Henegouwen M. C. C. M. Hulshof J. J. G. H. M. Bergman S. L. Meijer M. F. Bijlsma H. W. M. van Laarhoven |
| author_sort | A. Creemers |
| collection | DOAJ |
| description | Abstract In this study we aimed to investigate signaling pathways that drive therapy resistance in esophageal adenocarcinoma (EAC). Paraffin-embedded material was analyzed in two patient cohorts: (i) 236 EAC patients with a primary tumor biopsy and corresponding post neoadjuvant chemoradiotherapy (nCRT) resection; (ii) 66 EAC patients with resection and corresponding recurrence. Activity of six key cancer-related signaling pathways was inferred using the Bayesian inference method. When assessing pre- and post-nCRT samples, lower FOXO transcriptional activity was observed in poor nCRT responders compared to good nCRT responders (p = 0.0017). This poor responder profile was preserved in recurrences compared to matched resections (p = 0.0007). PI3K pathway activity, inversely linked with FOXO activity, was higher in CRT poor responder cell lines compared to CRT good responders. Poor CRT responder cell lines could be sensitized to CRT using PI3K inhibitors. To conclude, by using a novel method to measure signaling pathway activity on clinically available material, we identified an association of low FOXO transcriptional activity with poor response to nCRT. Targeting this pathway sensitized cells for nCRT, underlining its feasibility to select appropriate targeted therapies. |
| first_indexed | 2024-04-13T03:59:03Z |
| format | Article |
| id | doaj.art-b796bd80452e4486bd3a67a7544d6df4 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-04-13T03:59:03Z |
| publishDate | 2022-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-b796bd80452e4486bd3a67a7544d6df42022-12-22T03:03:32ZengBMCJournal of Translational Medicine1479-58762022-04-0120111110.1186/s12967-022-03376-wFOXO transcriptional activity is associated with response to chemoradiation in EACA. Creemers0A. P. van der Zalm1A. van de Stolpe2L. Holtzer3M. Stoffels4G. K. J. Hooijer5E. A. Ebbing6H. van Ooijen7A. G. C. van Brussel8E. M. G. Aussems-Custers9M. I. van Berge Henegouwen10M. C. C. M. Hulshof11J. J. G. H. M. Bergman12S. L. Meijer13M. F. Bijlsma14H. W. M. van Laarhoven15Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of AmsterdamLaboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of AmsterdamPhilips Molecular Pathway DiagnosticsPhilips Molecular Pathway DiagnosticsPhilips ResearchDepartment of Pathology, Cancer Center Amsterdam, Amsterdam UMC, University of AmsterdamLaboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of AmsterdamPhilips ResearchPhilips Molecular Pathway DiagnosticsPhilips ResearchDepartment of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of AmsterdamDepartment of Radiotherapy, Cancer Center Amsterdam, Amsterdam UMC, University of AmsterdamDepartment of Gastroenterology, Cancer Center Amsterdam, Amsterdam UMC, University of AmsterdamDepartment of Pathology, Cancer Center Amsterdam, Amsterdam UMC, University of AmsterdamLaboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of AmsterdamLaboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of AmsterdamAbstract In this study we aimed to investigate signaling pathways that drive therapy resistance in esophageal adenocarcinoma (EAC). Paraffin-embedded material was analyzed in two patient cohorts: (i) 236 EAC patients with a primary tumor biopsy and corresponding post neoadjuvant chemoradiotherapy (nCRT) resection; (ii) 66 EAC patients with resection and corresponding recurrence. Activity of six key cancer-related signaling pathways was inferred using the Bayesian inference method. When assessing pre- and post-nCRT samples, lower FOXO transcriptional activity was observed in poor nCRT responders compared to good nCRT responders (p = 0.0017). This poor responder profile was preserved in recurrences compared to matched resections (p = 0.0007). PI3K pathway activity, inversely linked with FOXO activity, was higher in CRT poor responder cell lines compared to CRT good responders. Poor CRT responder cell lines could be sensitized to CRT using PI3K inhibitors. To conclude, by using a novel method to measure signaling pathway activity on clinically available material, we identified an association of low FOXO transcriptional activity with poor response to nCRT. Targeting this pathway sensitized cells for nCRT, underlining its feasibility to select appropriate targeted therapies.https://doi.org/10.1186/s12967-022-03376-wEsophageal adenocarcinomaPathway analysisPredictiveNeoadjuvant chemoradiation therapy |
| spellingShingle | A. Creemers A. P. van der Zalm A. van de Stolpe L. Holtzer M. Stoffels G. K. J. Hooijer E. A. Ebbing H. van Ooijen A. G. C. van Brussel E. M. G. Aussems-Custers M. I. van Berge Henegouwen M. C. C. M. Hulshof J. J. G. H. M. Bergman S. L. Meijer M. F. Bijlsma H. W. M. van Laarhoven FOXO transcriptional activity is associated with response to chemoradiation in EAC Journal of Translational Medicine Esophageal adenocarcinoma Pathway analysis Predictive Neoadjuvant chemoradiation therapy |
| title | FOXO transcriptional activity is associated with response to chemoradiation in EAC |
| title_full | FOXO transcriptional activity is associated with response to chemoradiation in EAC |
| title_fullStr | FOXO transcriptional activity is associated with response to chemoradiation in EAC |
| title_full_unstemmed | FOXO transcriptional activity is associated with response to chemoradiation in EAC |
| title_short | FOXO transcriptional activity is associated with response to chemoradiation in EAC |
| title_sort | foxo transcriptional activity is associated with response to chemoradiation in eac |
| topic | Esophageal adenocarcinoma Pathway analysis Predictive Neoadjuvant chemoradiation therapy |
| url | https://doi.org/10.1186/s12967-022-03376-w |
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