Blockade of VEGF-C signaling inhibits lymphatic malformations driven by oncogenic PIK3CA mutation

Martínez-Corral, Inés; Zhang, Yan; Petkova, Milena; Ortsäter, Henrik; Sjöberg, Sofie; Castillo, Sandra D.; Brouillard, Pascal; Libbrecht, Louis; Saur, Dieter; Graupera, Mariona; Alitalo, Kari; Boon, Laurence M.; Vikkula, Miikka; Mäkinen, Taija

doi:10.1038/s41467-020-16496-y

Cited by 74 publications

(113 citation statements)

References 65 publications

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“…Endothelial cells also expressed p-S6R and p-4EBP1 (Fig. 1C), reflecting an mTOR pathway activation previously described in congenital vascular tumors and malformations [3].…”

Section: Patient Storysupporting

confidence: 76%

Neoadjuvant Everolimus for Adult Giant Mesenteric Cystic Lymphangioma with mTOR Pathway Activation

et al. 2021

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Cystic lymphangioma are rare benign vascular or lymphatic tumors, diagnosed mostly in newborns or children, that may become life-threatening because of local invasiveness. Surgical "en-bloc" resection with negative margins is the only curative treatment, but some patients are diagnosed with unresectable tumors. We describe the case of a young adult with giant unresectable mesenteric lymphangioma. Extensive pathological characterization as well as whole exome and transcriptome sequencing enabled us to identify

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“…Endothelial cells also expressed p-S6R and p-4EBP1 (Fig. 1C), reflecting an mTOR pathway activation previously described in congenital vascular tumors and malformations [3].…”

Section: Patient Storysupporting

confidence: 76%

Neoadjuvant Everolimus for Adult Giant Mesenteric Cystic Lymphangioma with mTOR Pathway Activation

et al. 2021

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“…Compensation was performed using the anti-rat/hamster compensation bead kit and the ArC amine reactive compensation bead kit (Life technologies). Single viable cells were gated as described above and in Martinez-Corral et al, 2020 and dead cells were excluded in the 355-UV laser dump channel. FMO controls were used to set up the subsequent gating scheme to obtain cell populations and quantification of proliferating cells.…”

Section: Methodsmentioning

confidence: 99%

EphrinB2-EphB4 signalling provides Rho-mediated homeostatic control of lymphatic endothelial cell junction integrity

Frye

Stritt

Ortsäter

et al. 2020

eLife

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Endothelial integrity is vital for homeostasis and adjusted to tissue demands. Although fluid uptake by lymphatic capillaries is a critical attribute of the lymphatic vasculature, the barrier function of collecting lymphatic vessels is also important by ensuring efficient fluid drainage as well as lymph node delivery of antigens and immune cells. Here, we identified the transmembrane ligand EphrinB2 and its receptor EphB4 as critical homeostatic regulators of collecting lymphatic vessel integrity. Conditional gene deletion in mice revealed that EphrinB2/EphB4 signalling is dispensable for blood endothelial barrier function, but required for stabilization of lymphatic endothelial cell (LEC) junctions in different organs of juvenile and adult mice. Studies in primary human LECs further showed that basal EphrinB2/EphB4 signalling controls junctional localisation of the tight junction protein CLDN5 and junction stability via Rac1/Rho-mediated regulation of cytoskeletal contractility. EphrinB2/EphB4 signalling therefore provides a potential therapeutic target to selectively modulate lymphatic vessel permeability and function.

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“…Recently, the combined treatment of VEGF-C trap and rapamycin, but neither treatment alone, were found to promote lesion regression in PIK3CA H1047R -driven lymphatic malformations, through lymphatic vasculature regression and blockage of LEC proliferation ( 141 ). This highlights the importance of combination therapy on both upstream and downstream elements of a mutant effector molecule, suggesting the combined impact of other signaling proteins in the generation of these physiological changes.…”

Section: The Akt Pathway and Lymphangiogenesismentioning

confidence: 99%

Ras Pathways on Prox1 and Lymphangiogenesis: Insights for Therapeutics

Bui

Hong

2020

Front. Cardiovasc. Med.

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Over the past couple of decades, lymphatics research has accelerated and gained a much-needed recognition in pathophysiology. As the lymphatic system plays heavy roles in interstitial fluid drainage, immune surveillance and lipid absorption, the ablation or excessive growth of this vasculature could be associated with many complications, from lymphedema to metastasis. Despite their growing importance in cancer, few anti-lymphangiogenic therapies exist today, as they have yet to pass phase 3 clinical trials and acquire FDA approval. As such, many studies are being done to better define the signaling pathways that govern lymphangiogenesis, in hopes of developing new therapeutic approaches to inhibit or stimulate this process. This review will cover our current understanding of the Ras signaling pathways and their interactions with Prox1, the master transcriptional switch involved in specifying lymphatic endothelial cell fate and lymphangiogenesis, in hopes of providing insights to lymphangiogenesis-based therapies.

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Blockade of VEGF-C signaling inhibits lymphatic malformations driven by oncogenic PIK3CA mutation

Cited by 74 publications

References 65 publications

Neoadjuvant Everolimus for Adult Giant Mesenteric Cystic Lymphangioma with mTOR Pathway Activation

Neoadjuvant Everolimus for Adult Giant Mesenteric Cystic Lymphangioma with mTOR Pathway Activation

EphrinB2-EphB4 signalling provides Rho-mediated homeostatic control of lymphatic endothelial cell junction integrity

Ras Pathways on Prox1 and Lymphangiogenesis: Insights for Therapeutics

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