The atypical KRASQ22K mutation directs TGF‐β response towards partial epithelial‐to‐mesenchymal transition in patient‐derived colorectal cancer tumoroids
Transforming growth factor beta (TGF‐β) exhibits complex and context‐dependent cellular responses. While it mostly induces tumor‐suppressive effects in early stages of tumorigenesis, tumor‐promoting properties are evident in advanced disease. This TGF‐β duality is still not fully understood, and whe...
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| Format: | Article |
| Language: | English |
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Wiley
2025-08-01
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| Series: | Molecular Oncology |
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| Online Access: | https://doi.org/10.1002/1878-0261.70014 |
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| author | Theresia Mair Philip König Milena Mijović Jessica Kalla Anil Baskan Loan Tran Kristina Draganić Pedro Morata Saldaña Carlos Uziel Pérez Malla Janette Pfneissl Andreas Tiefenbacher Julijan Kabiljo Velina S. Atanasova Lisa Wozelka‐Oltjan Leonhard Müllauer Michael Bergmann Raheleh Sheibani‐Tezerji Gerda Egger |
| author_facet | Theresia Mair Philip König Milena Mijović Jessica Kalla Anil Baskan Loan Tran Kristina Draganić Pedro Morata Saldaña Carlos Uziel Pérez Malla Janette Pfneissl Andreas Tiefenbacher Julijan Kabiljo Velina S. Atanasova Lisa Wozelka‐Oltjan Leonhard Müllauer Michael Bergmann Raheleh Sheibani‐Tezerji Gerda Egger |
| author_sort | Theresia Mair |
| collection | DOAJ |
| description | Transforming growth factor beta (TGF‐β) exhibits complex and context‐dependent cellular responses. While it mostly induces tumor‐suppressive effects in early stages of tumorigenesis, tumor‐promoting properties are evident in advanced disease. This TGF‐β duality is still not fully understood, and whether TGF‐β supports invasion and metastasis by influencing cancer cells directly, or rather through the stromal tumor compartment, remains a matter of debate. Here, we utilized a library of colorectal cancer (CRC) patient‐derived tumoroids (PDTs), representing a spectrum of tumor stages, to study cancer cell‐specific responses to TGF‐β. Using conditions allowing for the differentiation of PDTs, we observed TGF‐β‐induced tumor‐suppressive effects in early‐stage tumoroids, whereas more advanced tumoroids were less sensitive to the treatment. Notably, one tumoroid line harboring an atypical KRASQ22K mutation underwent partial epithelial‐to‐mesenchymal transition (EMT), which was associated with morphological changes and increased invasiveness. On a molecular level, this was accompanied by elevated expression of mesenchymal genes, as well as deregulation of pathways associated with matrix remodeling and cell adhesion. Our results suggest that tumor cell‐intrinsic responses to TGF‐β are critical in determining its tumor‐suppressive or tumor‐promoting effects. |
| format | Article |
| id | doaj-art-b69b56e87e7b46a4a01d71d3fe3a3a9b |
| institution | Kabale University |
| issn | 1574-7891 1878-0261 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj-art-b69b56e87e7b46a4a01d71d3fe3a3a9b2025-08-20T03:39:45ZengWileyMolecular Oncology1574-78911878-02612025-08-011982212223210.1002/1878-0261.70014The atypical KRASQ22K mutation directs TGF‐β response towards partial epithelial‐to‐mesenchymal transition in patient‐derived colorectal cancer tumoroidsTheresia Mair0Philip König1Milena Mijović2Jessica Kalla3Anil Baskan4Loan Tran5Kristina Draganić6Pedro Morata Saldaña7Carlos Uziel Pérez Malla8Janette Pfneissl9Andreas Tiefenbacher10Julijan Kabiljo11Velina S. Atanasova12Lisa Wozelka‐Oltjan13Leonhard Müllauer14Michael Bergmann15Raheleh Sheibani‐Tezerji16Gerda Egger17Department of Pathology Medical University of Vienna AustriaDepartment of Pathology Medical University of Vienna AustriaDepartment of Pathology Medical University of Vienna AustriaDepartment of Pathology Medical University of Vienna AustriaDepartment of Pathology Medical University of Vienna AustriaDepartment of Pathology Medical University of Vienna AustriaDepartment of Pathology Medical University of Vienna AustriaDepartment of Pathology Medical University of Vienna AustriaDepartment of Pathology Medical University of Vienna AustriaDepartment of Pathology Medical University of Vienna AustriaDepartment of Pathology Medical University of Vienna AustriaLudwig Boltzmann Institute Applied Diagnostics AustriaLudwig Boltzmann Institute Applied Diagnostics AustriaDepartment of Pathology Medical University of Vienna AustriaDepartment of Pathology Medical University of Vienna AustriaDepartment of General Surgery, Division of Visceral Surgery Medical University of Vienna AustriaDepartment of Pathology Medical University of Vienna AustriaDepartment of Pathology Medical University of Vienna AustriaTransforming growth factor beta (TGF‐β) exhibits complex and context‐dependent cellular responses. While it mostly induces tumor‐suppressive effects in early stages of tumorigenesis, tumor‐promoting properties are evident in advanced disease. This TGF‐β duality is still not fully understood, and whether TGF‐β supports invasion and metastasis by influencing cancer cells directly, or rather through the stromal tumor compartment, remains a matter of debate. Here, we utilized a library of colorectal cancer (CRC) patient‐derived tumoroids (PDTs), representing a spectrum of tumor stages, to study cancer cell‐specific responses to TGF‐β. Using conditions allowing for the differentiation of PDTs, we observed TGF‐β‐induced tumor‐suppressive effects in early‐stage tumoroids, whereas more advanced tumoroids were less sensitive to the treatment. Notably, one tumoroid line harboring an atypical KRASQ22K mutation underwent partial epithelial‐to‐mesenchymal transition (EMT), which was associated with morphological changes and increased invasiveness. On a molecular level, this was accompanied by elevated expression of mesenchymal genes, as well as deregulation of pathways associated with matrix remodeling and cell adhesion. Our results suggest that tumor cell‐intrinsic responses to TGF‐β are critical in determining its tumor‐suppressive or tumor‐promoting effects.https://doi.org/10.1002/1878-0261.70014colorectal cancerEMTKRAS mutationsorganoidspatient‐derived tumoroidsTGF‐β |
| spellingShingle | Theresia Mair Philip König Milena Mijović Jessica Kalla Anil Baskan Loan Tran Kristina Draganić Pedro Morata Saldaña Carlos Uziel Pérez Malla Janette Pfneissl Andreas Tiefenbacher Julijan Kabiljo Velina S. Atanasova Lisa Wozelka‐Oltjan Leonhard Müllauer Michael Bergmann Raheleh Sheibani‐Tezerji Gerda Egger The atypical KRASQ22K mutation directs TGF‐β response towards partial epithelial‐to‐mesenchymal transition in patient‐derived colorectal cancer tumoroids Molecular Oncology colorectal cancer EMT KRAS mutations organoids patient‐derived tumoroids TGF‐β |
| title | The atypical KRASQ22K mutation directs TGF‐β response towards partial epithelial‐to‐mesenchymal transition in patient‐derived colorectal cancer tumoroids |
| title_full | The atypical KRASQ22K mutation directs TGF‐β response towards partial epithelial‐to‐mesenchymal transition in patient‐derived colorectal cancer tumoroids |
| title_fullStr | The atypical KRASQ22K mutation directs TGF‐β response towards partial epithelial‐to‐mesenchymal transition in patient‐derived colorectal cancer tumoroids |
| title_full_unstemmed | The atypical KRASQ22K mutation directs TGF‐β response towards partial epithelial‐to‐mesenchymal transition in patient‐derived colorectal cancer tumoroids |
| title_short | The atypical KRASQ22K mutation directs TGF‐β response towards partial epithelial‐to‐mesenchymal transition in patient‐derived colorectal cancer tumoroids |
| title_sort | atypical krasq22k mutation directs tgf β response towards partial epithelial to mesenchymal transition in patient derived colorectal cancer tumoroids |
| topic | colorectal cancer EMT KRAS mutations organoids patient‐derived tumoroids TGF‐β |
| url | https://doi.org/10.1002/1878-0261.70014 |
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