MLKL deficiency in Braf V600E Pten −/− melanoma model results in a modest delay of nevi development and reduced lymph node dissemination in male mice
Abstract Cancers acquire several capabilities to survive the multistep process in carcinogenesis. Resisting cell death is one of them. Silencing of the necroptosis initiator Ripk3 occurs in a wide variety of cancer types including melanoma. Little is known about the role of the necroptosis execution...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-04-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-04819-4 |
| _version_ | 1818273403009761280 |
|---|---|
| author | Sofie Martens Nozomi Takahashi Gillian Blancke Niels Vandamme Hanne Verschuere Tatyana Divert Marnik Vuylsteke Geert Berx Peter Vandenabeele |
| author_facet | Sofie Martens Nozomi Takahashi Gillian Blancke Niels Vandamme Hanne Verschuere Tatyana Divert Marnik Vuylsteke Geert Berx Peter Vandenabeele |
| author_sort | Sofie Martens |
| collection | DOAJ |
| description | Abstract Cancers acquire several capabilities to survive the multistep process in carcinogenesis. Resisting cell death is one of them. Silencing of the necroptosis initiator Ripk3 occurs in a wide variety of cancer types including melanoma. Little is known about the role of the necroptosis executioner MLKL in tumor development. Studies often indicate opposing roles for MLKL as a tumor-suppressing or a tumor-promoting protein. This study investigates the role of MLKL during melanoma initiation and progression using a tamoxifen-inducible melanoma mouse model driven by melanocyte-specific overexpression of mutated Braf and simultaneous deletion of Pten (Braf V600E Pten −/− ). In this model we observed a clear sex difference: melanoma initiation and progression were faster in females mice. Mlkl deficiency in male mice resulted in a modest but significant reduction of nevi growth rate compared to the littermate control. In these mice, infiltration and expansion of melanoma cells in the inguinal lymph node were also modestly decreased. This is likely to be a consequence of the delay in nevi development. No significant difference was observed in the Mlkl-deficient condition in female mice in which melanoma development was faster. Overall, our results indicate that in this genetic model MLKL has a minor role during melanoma initiation and progression. |
| first_indexed | 2024-12-12T21:57:24Z |
| format | Article |
| id | doaj.art-77587f1f6b4b4d57a3677719136c1aaf |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-12T21:57:24Z |
| publishDate | 2022-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-77587f1f6b4b4d57a3677719136c1aaf2022-12-22T00:10:36ZengNature Publishing GroupCell Death and Disease2041-48892022-04-0113411010.1038/s41419-022-04819-4MLKL deficiency in Braf V600E Pten −/− melanoma model results in a modest delay of nevi development and reduced lymph node dissemination in male miceSofie Martens0Nozomi Takahashi1Gillian Blancke2Niels Vandamme3Hanne Verschuere4Tatyana Divert5Marnik Vuylsteke6Geert Berx7Peter Vandenabeele8VIB-UGent Center for Inflammation ResearchVIB-UGent Center for Inflammation ResearchCancer Research Institute Ghent (CRIG)Cancer Research Institute Ghent (CRIG)VIB-UGent Center for Inflammation ResearchVIB-UGent Center for Inflammation ResearchGnomixx BVCancer Research Institute Ghent (CRIG)VIB-UGent Center for Inflammation ResearchAbstract Cancers acquire several capabilities to survive the multistep process in carcinogenesis. Resisting cell death is one of them. Silencing of the necroptosis initiator Ripk3 occurs in a wide variety of cancer types including melanoma. Little is known about the role of the necroptosis executioner MLKL in tumor development. Studies often indicate opposing roles for MLKL as a tumor-suppressing or a tumor-promoting protein. This study investigates the role of MLKL during melanoma initiation and progression using a tamoxifen-inducible melanoma mouse model driven by melanocyte-specific overexpression of mutated Braf and simultaneous deletion of Pten (Braf V600E Pten −/− ). In this model we observed a clear sex difference: melanoma initiation and progression were faster in females mice. Mlkl deficiency in male mice resulted in a modest but significant reduction of nevi growth rate compared to the littermate control. In these mice, infiltration and expansion of melanoma cells in the inguinal lymph node were also modestly decreased. This is likely to be a consequence of the delay in nevi development. No significant difference was observed in the Mlkl-deficient condition in female mice in which melanoma development was faster. Overall, our results indicate that in this genetic model MLKL has a minor role during melanoma initiation and progression.https://doi.org/10.1038/s41419-022-04819-4 |
| spellingShingle | Sofie Martens Nozomi Takahashi Gillian Blancke Niels Vandamme Hanne Verschuere Tatyana Divert Marnik Vuylsteke Geert Berx Peter Vandenabeele MLKL deficiency in Braf V600E Pten −/− melanoma model results in a modest delay of nevi development and reduced lymph node dissemination in male mice Cell Death and Disease |
| title | MLKL deficiency in Braf V600E Pten −/− melanoma model results in a modest delay of nevi development and reduced lymph node dissemination in male mice |
| title_full | MLKL deficiency in Braf V600E Pten −/− melanoma model results in a modest delay of nevi development and reduced lymph node dissemination in male mice |
| title_fullStr | MLKL deficiency in Braf V600E Pten −/− melanoma model results in a modest delay of nevi development and reduced lymph node dissemination in male mice |
| title_full_unstemmed | MLKL deficiency in Braf V600E Pten −/− melanoma model results in a modest delay of nevi development and reduced lymph node dissemination in male mice |
| title_short | MLKL deficiency in Braf V600E Pten −/− melanoma model results in a modest delay of nevi development and reduced lymph node dissemination in male mice |
| title_sort | mlkl deficiency in braf v600e pten melanoma model results in a modest delay of nevi development and reduced lymph node dissemination in male mice |
| url | https://doi.org/10.1038/s41419-022-04819-4 |
| work_keys_str_mv | AT sofiemartens mlkldeficiencyinbrafv600eptenmelanomamodelresultsinamodestdelayofnevidevelopmentandreducedlymphnodedisseminationinmalemice AT nozomitakahashi mlkldeficiencyinbrafv600eptenmelanomamodelresultsinamodestdelayofnevidevelopmentandreducedlymphnodedisseminationinmalemice AT gillianblancke mlkldeficiencyinbrafv600eptenmelanomamodelresultsinamodestdelayofnevidevelopmentandreducedlymphnodedisseminationinmalemice AT nielsvandamme mlkldeficiencyinbrafv600eptenmelanomamodelresultsinamodestdelayofnevidevelopmentandreducedlymphnodedisseminationinmalemice AT hanneverschuere mlkldeficiencyinbrafv600eptenmelanomamodelresultsinamodestdelayofnevidevelopmentandreducedlymphnodedisseminationinmalemice AT tatyanadivert mlkldeficiencyinbrafv600eptenmelanomamodelresultsinamodestdelayofnevidevelopmentandreducedlymphnodedisseminationinmalemice AT marnikvuylsteke mlkldeficiencyinbrafv600eptenmelanomamodelresultsinamodestdelayofnevidevelopmentandreducedlymphnodedisseminationinmalemice AT geertberx mlkldeficiencyinbrafv600eptenmelanomamodelresultsinamodestdelayofnevidevelopmentandreducedlymphnodedisseminationinmalemice AT petervandenabeele mlkldeficiencyinbrafv600eptenmelanomamodelresultsinamodestdelayofnevidevelopmentandreducedlymphnodedisseminationinmalemice |