TGFβ signaling sensitizes MEKi-resistant human melanoma to targeted therapy-induced apoptosis
Abstract The TGFβ signaling pathway is known for its pleiotropic functions in a plethora of biological processes. In melanoma, TGFβ signaling promotes invasiveness and metastasis formation. However, its involvement in the response to therapy is controversial. While several studies have linked TGFβ s...
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| Format: | Article |
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Nature Publishing Group
2024-12-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-07305-1 |
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| author | Benjamin Loos Adrian Salas-Bastos Anna Nordin Julien Debbache Salome Stierli Phil F. Cheng Stefanie Rufli Conrad Wyss Mitchell P. Levesque Reinhard Dummer Wendy Wei-Lynn Wong Steve Pascolo Claudio Cantù Lukas Sommer |
| author_facet | Benjamin Loos Adrian Salas-Bastos Anna Nordin Julien Debbache Salome Stierli Phil F. Cheng Stefanie Rufli Conrad Wyss Mitchell P. Levesque Reinhard Dummer Wendy Wei-Lynn Wong Steve Pascolo Claudio Cantù Lukas Sommer |
| author_sort | Benjamin Loos |
| collection | DOAJ |
| description | Abstract The TGFβ signaling pathway is known for its pleiotropic functions in a plethora of biological processes. In melanoma, TGFβ signaling promotes invasiveness and metastasis formation. However, its involvement in the response to therapy is controversial. While several studies have linked TGFβ signaling to elevated resistance to targeted therapy in melanoma, separate findings have indicated a favorable treatment response through TGFβ-mediated increase of cell death. We now found that the outcome of TGFβ signaling in the context of targeted therapy is dose dependent. Unlike low doses, high levels of TGFβ signal activation induce apoptosis upon simultaneous MAPK pathway inhibition, even in targeted therapy resistant melanoma cell lines. Using transcriptomic analyses, combined with genomic target identification of the critical TGFβ signaling effector SMAD4, we demonstrate that parallel activation of TGFβ signaling and MAPK pathway inhibition causes a complete switch of TGFβ target genes from promoting pro-invasive processes to fueling pro-apoptotic pathways. Investigations of underlying mechanisms identified a novel apoptosis-inducing gene signature. Functional validation of signature members highlighted a central role of the pro-apoptotic BCL2 family member BCL2L11 (BIM) in mediating apoptosis in this condition. Using a modified, synthetic version of the TGFB1 mRNA for intra-tumoral injections, we additionally showcase a potential therapeutic application of this treatment combination. |
| format | Article |
| id | doaj-art-ffa3a422e75549078e48baa042793f68 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-ffa3a422e75549078e48baa042793f682024-12-22T12:51:01ZengNature Publishing GroupCell Death and Disease2041-48892024-12-01151211810.1038/s41419-024-07305-1TGFβ signaling sensitizes MEKi-resistant human melanoma to targeted therapy-induced apoptosisBenjamin Loos0Adrian Salas-Bastos1Anna Nordin2Julien Debbache3Salome Stierli4Phil F. Cheng5Stefanie Rufli6Conrad Wyss7Mitchell P. Levesque8Reinhard Dummer9Wendy Wei-Lynn Wong10Steve Pascolo11Claudio Cantù12Lukas Sommer13University of Zürich, Institute of AnatomyUniversity of Zürich, Institute of AnatomyWallenberg Centre for Molecular Medicine, Linköping UniversityUniversity of Zürich, Institute of AnatomyUniversity of Zürich, Institute of AnatomyUniversity of Zürich Hospital, University of Zürich, Department of DermatologyUniversity of Zurich, Institute of Experimental ImmunologyUniversity of Zürich Hospital, University of Zürich, Department of DermatologyUniversity of Zürich Hospital, University of Zürich, Department of DermatologyUniversity of Zürich Hospital, University of Zürich, Department of DermatologyUniversity of Zurich, Institute of Experimental ImmunologyUniversity of Zürich Hospital, University of Zürich, Department of DermatologyWallenberg Centre for Molecular Medicine, Linköping UniversityUniversity of Zürich, Institute of AnatomyAbstract The TGFβ signaling pathway is known for its pleiotropic functions in a plethora of biological processes. In melanoma, TGFβ signaling promotes invasiveness and metastasis formation. However, its involvement in the response to therapy is controversial. While several studies have linked TGFβ signaling to elevated resistance to targeted therapy in melanoma, separate findings have indicated a favorable treatment response through TGFβ-mediated increase of cell death. We now found that the outcome of TGFβ signaling in the context of targeted therapy is dose dependent. Unlike low doses, high levels of TGFβ signal activation induce apoptosis upon simultaneous MAPK pathway inhibition, even in targeted therapy resistant melanoma cell lines. Using transcriptomic analyses, combined with genomic target identification of the critical TGFβ signaling effector SMAD4, we demonstrate that parallel activation of TGFβ signaling and MAPK pathway inhibition causes a complete switch of TGFβ target genes from promoting pro-invasive processes to fueling pro-apoptotic pathways. Investigations of underlying mechanisms identified a novel apoptosis-inducing gene signature. Functional validation of signature members highlighted a central role of the pro-apoptotic BCL2 family member BCL2L11 (BIM) in mediating apoptosis in this condition. Using a modified, synthetic version of the TGFB1 mRNA for intra-tumoral injections, we additionally showcase a potential therapeutic application of this treatment combination.https://doi.org/10.1038/s41419-024-07305-1 |
| spellingShingle | Benjamin Loos Adrian Salas-Bastos Anna Nordin Julien Debbache Salome Stierli Phil F. Cheng Stefanie Rufli Conrad Wyss Mitchell P. Levesque Reinhard Dummer Wendy Wei-Lynn Wong Steve Pascolo Claudio Cantù Lukas Sommer TGFβ signaling sensitizes MEKi-resistant human melanoma to targeted therapy-induced apoptosis Cell Death and Disease |
| title | TGFβ signaling sensitizes MEKi-resistant human melanoma to targeted therapy-induced apoptosis |
| title_full | TGFβ signaling sensitizes MEKi-resistant human melanoma to targeted therapy-induced apoptosis |
| title_fullStr | TGFβ signaling sensitizes MEKi-resistant human melanoma to targeted therapy-induced apoptosis |
| title_full_unstemmed | TGFβ signaling sensitizes MEKi-resistant human melanoma to targeted therapy-induced apoptosis |
| title_short | TGFβ signaling sensitizes MEKi-resistant human melanoma to targeted therapy-induced apoptosis |
| title_sort | tgfβ signaling sensitizes meki resistant human melanoma to targeted therapy induced apoptosis |
| url | https://doi.org/10.1038/s41419-024-07305-1 |
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