Hyperactive KRAS/MAPK signaling disrupts normal lymphatic vessel architecture and function
Complex lymphatic anomalies (CLAs) are sporadically occurring diseases caused by the maldevelopment of lymphatic vessels. We and others recently reported that somatic activating mutations in KRAS can cause CLAs. However, the mechanisms by which activating KRAS mutations cause CLAs are poorly underst...
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| Format: | Article |
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Frontiers Media S.A.
2023-09-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2023.1276333/full |
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| author | Lorenzo M. Fernandes Jeffrey Tresemer Jing Zhang Jonathan J. Rios Jonathan J. Rios Joshua P. Scallan Michael T. Dellinger Michael T. Dellinger |
| author_facet | Lorenzo M. Fernandes Jeffrey Tresemer Jing Zhang Jonathan J. Rios Jonathan J. Rios Joshua P. Scallan Michael T. Dellinger Michael T. Dellinger |
| author_sort | Lorenzo M. Fernandes |
| collection | DOAJ |
| description | Complex lymphatic anomalies (CLAs) are sporadically occurring diseases caused by the maldevelopment of lymphatic vessels. We and others recently reported that somatic activating mutations in KRAS can cause CLAs. However, the mechanisms by which activating KRAS mutations cause CLAs are poorly understood. Here, we show that KRASG12D expression in lymphatic endothelial cells (LECs) during embryonic development impairs the formation of lymphovenous valves and causes the enlargement of lymphatic vessels. We demonstrate that KRASG12D expression in primary human LECs induces cell spindling, proliferation, and migration. It also increases AKT and ERK1/2 phosphorylation and decreases the expression of genes that regulate the maturation of lymphatic vessels. We show that MEK1/2 inhibition with the FDA-approved drug trametinib suppresses KRASG12D-induced morphological changes, proliferation, and migration. Trametinib also decreases ERK1/2 phosphorylation and increases the expression of genes that regulate the maturation of lymphatic vessels. We also show that trametinib and Cre-mediated expression of a dominant-negative form of MEK1 (Map2k1K97M) suppresses KRASG12D-induced lymphatic vessel hyperplasia in embryos. Last, we demonstrate that conditional knockout of wild-type Kras in LECs does not affect the formation or function of lymphatic vessels. Together, our data indicate that KRAS/MAPK signaling must be tightly regulated during embryonic development for the proper development of lymphatic vessels and further support the testing of MEK1/2 inhibitors for treating CLAs. |
| first_indexed | 2024-03-11T21:54:03Z |
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| id | doaj.art-ba2b069fed614929b94de62055977d42 |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-04-24T23:58:37Z |
| publishDate | 2023-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-ba2b069fed614929b94de62055977d422024-03-14T10:51:12ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2023-09-011110.3389/fcell.2023.12763331276333Hyperactive KRAS/MAPK signaling disrupts normal lymphatic vessel architecture and functionLorenzo M. Fernandes0Jeffrey Tresemer1Jing Zhang2Jonathan J. Rios3Jonathan J. Rios4Joshua P. Scallan5Michael T. Dellinger6Michael T. Dellinger7Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, United StatesHamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, United StatesMcArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, United StatesCenter for Pediatric Bone Biology and Translational Research, Scottish Rite for Children, Dallas, TX, United StatesMcDermott Center for Human Growth and Development, Dallas, TX, United StatesDepartment of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, United StatesHamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, United StatesDepartment of Surgery, UT Southwestern Medical Center, Dallas, TX, United StatesComplex lymphatic anomalies (CLAs) are sporadically occurring diseases caused by the maldevelopment of lymphatic vessels. We and others recently reported that somatic activating mutations in KRAS can cause CLAs. However, the mechanisms by which activating KRAS mutations cause CLAs are poorly understood. Here, we show that KRASG12D expression in lymphatic endothelial cells (LECs) during embryonic development impairs the formation of lymphovenous valves and causes the enlargement of lymphatic vessels. We demonstrate that KRASG12D expression in primary human LECs induces cell spindling, proliferation, and migration. It also increases AKT and ERK1/2 phosphorylation and decreases the expression of genes that regulate the maturation of lymphatic vessels. We show that MEK1/2 inhibition with the FDA-approved drug trametinib suppresses KRASG12D-induced morphological changes, proliferation, and migration. Trametinib also decreases ERK1/2 phosphorylation and increases the expression of genes that regulate the maturation of lymphatic vessels. We also show that trametinib and Cre-mediated expression of a dominant-negative form of MEK1 (Map2k1K97M) suppresses KRASG12D-induced lymphatic vessel hyperplasia in embryos. Last, we demonstrate that conditional knockout of wild-type Kras in LECs does not affect the formation or function of lymphatic vessels. Together, our data indicate that KRAS/MAPK signaling must be tightly regulated during embryonic development for the proper development of lymphatic vessels and further support the testing of MEK1/2 inhibitors for treating CLAs.https://www.frontiersin.org/articles/10.3389/fcell.2023.1276333/fullcomplex lymphatic anomalyKRAStrametiniblymphangiogenesislymphatic malformationGorham-Stout disease |
| spellingShingle | Lorenzo M. Fernandes Jeffrey Tresemer Jing Zhang Jonathan J. Rios Jonathan J. Rios Joshua P. Scallan Michael T. Dellinger Michael T. Dellinger Hyperactive KRAS/MAPK signaling disrupts normal lymphatic vessel architecture and function Frontiers in Cell and Developmental Biology complex lymphatic anomaly KRAS trametinib lymphangiogenesis lymphatic malformation Gorham-Stout disease |
| title | Hyperactive KRAS/MAPK signaling disrupts normal lymphatic vessel architecture and function |
| title_full | Hyperactive KRAS/MAPK signaling disrupts normal lymphatic vessel architecture and function |
| title_fullStr | Hyperactive KRAS/MAPK signaling disrupts normal lymphatic vessel architecture and function |
| title_full_unstemmed | Hyperactive KRAS/MAPK signaling disrupts normal lymphatic vessel architecture and function |
| title_short | Hyperactive KRAS/MAPK signaling disrupts normal lymphatic vessel architecture and function |
| title_sort | hyperactive kras mapk signaling disrupts normal lymphatic vessel architecture and function |
| topic | complex lymphatic anomaly KRAS trametinib lymphangiogenesis lymphatic malformation Gorham-Stout disease |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2023.1276333/full |
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