Introduction of Mutant GNAQ into Endothelial Cells Induces a Vascular Malformation Phenotype with Therapeutic Response to Imatinib

Sasaki, Maiko; Jung, Yoonhee; North, Paula E.; Elsey, Justin; Choate, Keith; Toussaint, M. Andrew; Huang, Chichi; Radi, Rakan; Perricone, Adam; Corcés, Victor G.; Arbiser, Jack L.

doi:10.3390/cancers14020413

Cited by 12 publications

(5 citation statements)

References 35 publications

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“…A second xenograft model by Sasaki and colleagues, based on murine ECs expressing GNAQ p.Q209L, confirmed that the GNAQ -mutant ECs could form enlarged, ectatic vessels upon subcutaneous injection into mice ( 63 ).…”

Section: Models Of Cm/sws and Other Gnaq -Related ...mentioning

confidence: 88%

Capillary malformations

Hammill,

Boscolo

2024

Journal of Clinical Investigation

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Capillary malformation (CM), or port wine birthmark, is a cutaneous congenital vascular anomaly that occurs in 0.1%–2% of newborns. Patients with a CM localized on the forehead have an increased risk of developing a neurocutaneous disorder called encephalotrigeminal angiomatosis or Sturge-Weber syndrome (SWS), with complications including seizure, developmental delay, glaucoma, and vision loss. In 2013, a groundbreaking study revealed causative activating somatic mutations in the gene ( GNAQ ) encoding guanine nucleotide–binding protein Q subunit α (Gαq) in CM and SWS patient tissues. In this Review, we discuss the disease phenotype, the causative GNAQ mutations, and their cellular origin. We also present the endothelial Gαq-related signaling pathways, the current animal models to study CM and its complications, and future options for therapeutic treatment. Further work remains to fully elucidate the cellular and molecular mechanisms underlying the formation and maintenance of the abnormal vessels.

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Section: Models Of Cm/sws and Other Gnaq -Related ...mentioning

confidence: 88%

Capillary malformations

Hammill,

Boscolo

2024

Journal of Clinical Investigation

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“…Multiple candidates known to affect vascular function are inhibited either selectively or more potently by nilotinib compared to imatinib. Cell-free kinase inhibition studies and proteomic analyses have identified differential inhibition by nilotinib of multiple targets including TEK, SRC, KDR, FLT4, MAPK14, JAK1, DDR1, KIT, and PDGFRB 7 – 9 , 27 . Which target(s) are central to the mechanism of NAD remains to be assessed in detail.…”

Section: Discussionmentioning

confidence: 99%

“…Our work demonstrates that nilotinib has multiple distinct phenotypic effects on ECs, and these distinct effects could either represent independent off-target mechanisms or result from inhibition of a common pathway. Of note, while off-target inhibition likely contributes to NAD pathogenesis, the effect of nilotinib on off-target pathways may be therapeutic in other diseases such as Sturge-Weber Syndrome 27 .…”

Section: Discussionmentioning

confidence: 99%

Nilotinib-induced alterations in endothelial cell function recapitulate clinical vascular phenotypes independent of ABL1

Pinheiro,

DeKeyser,

Lenny

et al. 2024

Sci Rep

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Nilotinib is a highly effective treatment for chronic myeloid leukemia but has been consistently associated with the development of nilotinib-induced arterial disease (NAD) in a subset of patients. To date, which cell types mediate this effect and whether NAD results from on-target mechanisms is unknown. We utilized human induced pluripotent stem cells (hiPSCs) to generate endothelial cells and vascular smooth muscle cells for in vitro study of NAD. We found that nilotinib adversely affects endothelial proliferation and migration, in addition to increasing intracellular nitric oxide. Nilotinib did not alter endothelial barrier function or lipid uptake. No effect of nilotinib was observed in vascular smooth muscle cells, suggesting that NAD is primarily mediated through endothelial cells. To evaluate whether NAD results from enhanced inhibition of ABL1, we generated multiple ABL1 knockout lines. The effects of nilotinib remained unchanged in the absence of ABL1, suggesting that NAD results from off- rather than on-target signaling. The model established in the present study can be applied to future mechanistic and patient-specific pharmacogenomic studies.

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“…Heterogeneity of malignant cells and various stromal cellular components determine the diverse expression of different growth factors and cytokines. Platelet-derived growth factors (PDGFs) are commonly expressed in tumors and target stromal fibroblasts and perivascular cells through binding to platelet-derived growth factor receptors (PDGFRs) including PDGFRα or PDGFRβ [23,[27][28][29]. While angiogenic endothelial cell-derived PDGFs promote the recruitment of pericytes onto newly formed vessels [30][31][32], high levels of tumor cell-derived PDGFs can ablate pericytes from tumor vasculatures [33][34][35].…”

Section: Introductionmentioning

confidence: 99%

Perivascular localized cells commit erythropoiesis in PDGF‐B‐expressing solid tumors

Hosaka

Wang

Zhang

et al. 2023

Cancer Communications

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Background Tumors possess incessant growth features, and expansion of their masses demands sufficient oxygen supply by red blood cells (RBCs). In adult mammals, the bone marrow (BM) is the main organ regulating hematopoiesis with dedicated manners. Other than BM, extramedullary hematopoiesis is discovered in various pathophysiological settings. However, whether tumors can contribute to hematopoiesis is completely unknown. Accumulating evidence shows that, in the tumor microenvironment (TME), perivascular localized cells retain progenitor cell properties and can differentiate into other cells. Here, we sought to better understand whether and how perivascular localized pericytes in tumors manipulate hematopoiesis. Methods To test if vascular cells can differentiate into RBCs, genome‐wide expression profiling was performed using mouse‐derived pericytes. Genetic tracing of perivascular localized cells employing NG2‐CreERT2:R26R‐tdTomato mouse strain was used to validate the findings in vivo. Fluorescence‐activated cell sorting (FACS), single‐cell sequencing, and colony formation assays were applied for biological studies. The production of erythroid differentiation‐specific cytokine, erythropoietin (EPO), in TME was checked using quantitative polymerase chain reaction (qPCR), enzyme‐linked immunosorbent assay (ELISA, magnetic‐activated cell sorting and immunohistochemistry. To investigate BM function in tumor erythropoiesis, BM transplantation mouse models were employed. Results Genome‐wide expression profiling showed that in response to platelet‐derived growth factor subunit B (PDGF‐B), neural/glial antigen 2 (NG2)+ perivascular localized cells exhibited hematopoietic stem and progenitor‐like features and underwent differentiation towards the erythroid lineage. PDGF‐B simultaneously targeted cancer‐associated fibroblasts to produce high levels of EPO, a crucial hormone that necessitates erythropoiesis. FACS analysis using genetic tracing of NG2+ cells in tumors defined the perivascular localized cell‐derived subpopulation of hematopoietic cells. Single‐cell sequencing and colony formation assays validated the fact that, upon PDGF‐B stimulation, NG2+ cells isolated from tumors acted as erythroblast progenitor cells, which were distinctive from the canonical BM hematopoietic stem cells. Conclusions Our data provide a new concept of hematopoiesis within tumor tissues and novel mechanistic insights into perivascular localized cell‐derived erythroid cells within TME. Targeting tumor hematopoiesis is a novel therapeutic concept for treating various cancers that may have profound impacts on cancer therapy.

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Introduction of Mutant GNAQ into Endothelial Cells Induces a Vascular Malformation Phenotype with Therapeutic Response to Imatinib

Cited by 12 publications

References 35 publications

Capillary malformations

Capillary malformations

Nilotinib-induced alterations in endothelial cell function recapitulate clinical vascular phenotypes independent of ABL1

Perivascular localized cells commit erythropoiesis in PDGF‐B‐expressing solid tumors

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