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Updated: Jun 20, 2026
In Vivo Inhibition of MicroRNA to Decrease Tumor Growth in Mice
Published on: August 23, 2019
MEK inhibition reduced vascular tumor growth and coagulopathy in a mouse model with hyperactive GNAQ
Sandra Schrenk1,2, Lindsay J Bischoff1,3, Jillian Goines1
1Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Abstract:
Activating non-inherited mutations in the guanine nucleotide-binding protein G(q) subunit alpha (GNAQ) gene family have been identified in childhood vascular tumors. Patients experience extensive disfigurement, chronic pain and severe complications including a potentially lethal coagulopathy termed Kasabach-Merritt phenomenon. Animal models for this class of vascular tumors do not exist. This has severely hindered the discovery of the molecular consequences of GNAQ mutations in the vasculature and, in turn, the preclinical development of effective targeted therapies. Here we report a mouse model expressing hyperactive mutant GNAQ in endothelial cells. Mutant mice develop vascular and coagulopathy phenotypes similar to those seen in patients. Mechanistically, by transcriptomic analysis we demonstrate increased mitogen activated protein kinase signaling in the mutant endothelial cells. Targeting of this pathway with Trametinib suppresses the tumor growth by reducing vascular cell proliferation and permeability. Trametinib also prevents the development of coagulopathy and improves mouse survival.
Insights
Researchers developed a new mouse model for GNAQ-mutant vascular tumors, crucial for studying childhood cancer. This model mimics patient symptoms and shows that targeting MAPK signaling with Trametinib effectively treats these tumors and related coagulopathy.
Area of Science:
- Oncology
- Genetics
- Vascular Biology
Background:
- Activating GNAQ gene mutations cause aggressive childhood vascular tumors.
- Patients suffer disfigurement, pain, and life-threatening Kasabach-Merritt phenomenon.
- Lack of animal models impedes understanding GNAQ mutations and developing targeted therapies.
Purpose of the Study:
- To create and characterize a novel mouse model for GNAQ-mutant vascular tumors.
- To investigate the molecular mechanisms driving tumor development and associated coagulopathy.
- To evaluate the efficacy of targeted therapies in this preclinical model.
Main Methods:
- Generated a mouse model with hyperactive mutant GNAQ in endothelial cells.
- Phenotypic analysis of vascular and coagulopathy traits.
- Transcriptomic analysis to identify signaling pathway alterations.
- Pharmacological inhibition of the mitogen-activated protein kinase (MAPK) pathway using Trametinib.
Main Results:
- Mutant mice exhibited vascular tumors and coagulopathy mirroring human disease.
- Transcriptomics revealed elevated MAPK signaling in mutant endothelial cells.
- Trametinib treatment suppressed tumor growth by reducing proliferation and permeability.
- Trametinib prevented coagulopathy and improved survival rates in mutant mice.
Conclusions:
- The developed mouse model accurately recapitulates GNAQ-mutant vascular tumors and associated coagulopathy.
- MAPK signaling is a key driver of GNAQ-mutant vascular tumors.
- Targeting MAPK signaling with Trametinib offers a promising therapeutic strategy for these conditions.
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