The Proteomic Landscape of CTNNB1 Mutated Low-Grade Early-Stage Endometrial Carcinomas
Endometrial carcinoma is the most frequent gynecologic malignancy in western countries. In recent years, mutations in <i>CTNNB1</i> have been associated with worse prognosis in low-risk carcinomas. However, there is a lack of understanding of the proteomic implications of <i>CTNNB1</i> mutations in this type of tumor. In this study, we performed shotgun proteomics using Formalin-Fixed Paraffin-Embedded (FFPE) tissue samples of <i>CTNNB1</i> mutated and wild-type low-risk endometrial carcinomas. A publicly available proteomic and transcriptomic database was used to validate results. Differential protein expression and Gene Set Enrichment Analysis revealed dysregulation of pathways associated with cell keratinization, immune response modulation, and intracellular calcium regulation. <i>CTNNB1</i> mutated tumors showed immune dysregulation at multiple levels including cytokine secretion, cell adhesion, and lymphocyte activation. These results were supported by tissue multiplex immunofluorescence analysis, demonstrating reduced CD8 tumor-infiltrating lymphocytes and different immune spatial interaction patterns. Intracellular calcium dysfunction was associated with key transcript dysregulation. We found an increased expression of CAMK2A and ROR2, suggesting a potential role for non-canonical Wnt pathway activation in <i>CTNNB1</i> mutated tumors.
Authors
- Marta Mendiola (ORCID: https://orcid.org/0000-0002-2463-1304)
- Vivian de los Rı́os (ORCID: https://orcid.org/0000-0001-5582-6879)
- Alberto Berjón (ORCID: https://orcid.org/0000-0002-3467-106X)
- Rodrigo Barderas (ORCID: https://orcid.org/0000-0003-3539-7469)
- Carlos E. de Andrea (ORCID: https://orcid.org/0000-0002-7628-8050)
- Laura Yébenes (ORCID: https://orcid.org/0000-0001-7345-9312)
- Ana Montero‐Calle (ORCID: https://orcid.org/0000-0001-5141-0454)
- Álvaro López‐Janeiro (ORCID: https://orcid.org/0000-0002-5744-3115)
- David Hardisson (ORCID: https://orcid.org/0000-0002-2183-3699)
- Raluca Alexandru (ORCID: https://orcid.org/0009-0002-1903-5636)
- Victoria Heredia-Soto (ORCID: https://orcid.org/0000-0002-0704-7958)
- Andrés Redondo (ORCID: https://orcid.org/0000-0002-7257-5642)
- Alberto Peláez‐García (ORCID: https://orcid.org/0000-0002-5401-3216)
- Ignacio Ruz‐Caracuel (ORCID: https://orcid.org/0000-0002-2298-4683)
- E Brizzi
Institutions
- Instituto Cajal (ES)
- Hospital Universitario La Paz (ES)
- Instituto de Salud Carlos III (ES)
- Hospital La Paz Institute for Health Research (ES)
- Madrid Health Service (ES)
- Instituto Ramón y Cajal de Investigación Sanitaria (ES)
- Clinica Universidad de Navarra (ES)
- Hospital Universitario Puerta del Mar (ES)
- Centro de Investigaciones Biológicas Margarita Salas (ES)
- Unidad Funcional de Investigación de Enfermedades Crónicas (ES)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- Hospital Universitario Ramón y Cajal (ES)
- Universidad Autónoma de Madrid (ES)
Publication Details
- Journal
- Cells
- Published
- 2025-10-27
- DOI
- https://doi.org/10.3390/cells14211676
- Citations
- 2
- Primary Topic
- Endometrial and Cervical Cancer Treatments
- Type
- article
- Field-Weighted Citation Impact
- 4.11