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Introduction
Additional affiliations
September 2020 - November 2021
May 2019 - present
November 2018 - present
Education
February 2018 - September 2020
February 2016 - January 2018
February 2015 - January 2016
Publications
Publications (72)
Secondary lymphedema (LE) following breast cancer‐related surgery is a life‐long complication, which currently has no cure. LE induces significant regional adipose tissue deposition, requiring liposuction as a treatment. Here, we aimed to elucidate the transcriptional, metabolomic, and lipidomic signature of the adipose tissue developed due to the...
Discovery of meningeal lymphatic vessels (LVs) in the dura mater, also known as dural LVs (dLVs) that depend on vascular endothelial growth factor C expression, has raised interest in their possible involvement in Alzheimer’s disease (AD). Here we find that in the APdE9 and 5xFAD mouse models of AD, dural amyloid-β (Aβ) is confined to blood vessels...
Macrophage Clever-1 contributes to impaired antigen presentation and suppression of anti-tumor immunity. This first-in-human trial investigates the safety and tolerability of Clever-1 blockade with bexmarilimab in patients with treatment-refractory solid tumors and assesses preliminary anti-tumor efficacy, pharmacodynamics, and immunologic correlat...
Despite strong indications that melanoma interaction with lymphatic vessels actively promotes melanoma progression, the molecular mechanisms are not yet completely understood. To characterize molecular factors of this crosstalk we established human primary lymphatic endothelial cell (LEC) co-cultures with human melanoma cell lines. Here, we show th...
Objective: Secondary lymphedema (LE) following breast cancer surgery is a life-long complication, which currently has no cure. LE induces significant regional adipose tissue deposition, requiring liposuction as a treatment. Here, we aimed to elucidate the transcriptional, metabolomic, and lipidomic signature of the adipose tissue developed due to t...
The small intestine is an excellent model for studying changes in vasculature in response to different diseases or gene deletions. Here, we present a protocol for whole-mount immunofluorescence staining of blood and lymphatic vessels in the adult mouse small intestine. We describe the steps for perfusion fixation, tissue sample preparation, immunof...
Despite strong indications that melanoma interaction with lymphatic vessels actively promotes melanoma progression, the molecular mechanisms are not yet completely understood. To characterize molecular factors of this crosstalk we established human primary lymphatic endothelial cell (LEC) co-cultures with human melanoma cell lines. Here, we show th...
Clever-1 expression in macrophages contributes to impaired antigen presentation and suppression of anti-tumor immunity. This first-in-human trial was designed to investigate the safety and tolerability of Clever-1 blockade in patients with treatment-refractory solid tumors and to assess preliminary anti- tumor efficacy, pharmacodynamics, and immuno...
The recent discovery of lymphatic vessels (LVs) in the dura mater, the outermost layer of meninges around the central nervous system (CNS), has opened a possibility for the development of alternative therapeutics for CNS disorders. The vascular endothelial growth factor C (VEGF-C)/VEGF receptor 3 (VEGFR3) signaling pathway is essential for the deve...
Leukocytes and resident cells in the arterial wall contribute to atherosclerosis, especially at sites of disturbed blood flow. Expression of endothelial Tie1 receptor tyrosine kinase is enhanced at these sites, and attenuation of its expression reduces atherosclerotic burden and decreases inflammation. However, Tie2 tyrosine kinase function in athe...
Purpose of review: Lymphatic vessels are found in most tissues, with the exception of the cornea and the central nervous system. Tissues that have high exposure to antigens, such as the skin and the intestine, have especially extensive lymphatic vascular networks. Despite being densely vascularized with blood vessels, adipose tissue is poorly perme...
Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are quintessential for the development and maintenance of blood and lymphatic vessels. However, genetic interactions between the VEGFRs are poorly understood. VEGFR2 is the dominant receptor that is required for the growth and survival of the endothelium, whereas deletion of V...
Rationale Successful recovery from acute lung injury requires inhibition of neutrophil influx and clearance of apoptotic neutrophils. However, the mechanisms underlying recovery remain unclear.
Objectives We investigated the ameliorative effects of vascular endothelial growth factor receptor-3 (VEGFR-3)/VEGF-C signaling in macrophages in lipopolys...
Tryptophan catabolism is a major metabolic pathway utilized by several professional and non-professional antigen presenting cells to maintain immunological tolerance. Here we report that 3-hydroxy-l-kynurenamine (3-HKA) is a biogenic amine produced via an alternative pathway of tryptophan metabolism. In vitro, 3-HKA has an anti-inflammatory profile...
Obesity and its comorbidities like diabetes, hypertension and other cardiovascular disorders are the leading causes of death and disability worldwide. Metabolic diseases cause vascular dysfunction and loss of capillaries termed capillary rarefaction. Interestingly, obesity seems to affect capillary beds in an organ-specific manner, causing morpholo...
The lymphatic vascular system plays important roles in the control of tissue fluid homeostasis and immune responses. While VEGF-A-induced angiogenesis promotes hair follicle (HF) growth, the potential role of lymphatic vessels (LVs) in HF cycling has remained unknown. In this study, we found that LVs are localized in close proximity to the HF bulge...
Highly selective by nature, the blood-brain barrier (BBB) is essential for the brain homeostasis in physiological conditions. However, in the context of brain tumors, the molecular selectivity of BBB also shields the neoplastic cells by blocking the delivery of peripherally administered chemotherapies. The development of novel drugs (including nano...
VEGF-C is an important mediator of lymphangiogenesis and has been shown to alleviate chronic inflammation in a variety of disease models. In this study, we investigated whether targeted delivery of VEGF-C to sites of inflammation and site-specific activation of lymphatic vessels would represent a clinically feasible strategy for treating chronic sk...
The lymphatic vessels can be selectively stimulated to grow in adult mice, rats and pigs by application of viral vectors expressing the lymphangiogenic factors VEGF-C or VEGF-D. Vice versa, lymphangiogenesis in various pathological settings can be inhibited by the blocking of the VEGF-C/VEGFR3 interaction using a ligand-binding soluble form of VEGF...
Vascular endothelial growth factors (VEGFs) are best known for their involvement in orchestrating the development and maintenance of the blood and lymphatic vascular systems. VEGFs are secreted by a variety of cells and they bind to their cognate tyrosine kinase VEGF receptors (VEGFRs) in endothelial cells to elicit various downstream effects. In r...
Thrombospondin-2 (TSP2) is an anti-angiogenic matricellular protein that inhibits tumor growth and angiogenesis. Tumor-associated blood vascular endothelial cells (BECs) were isolated from human invasive bladder cancers and from matched normal bladder tissue by immuno-laser capture microdissection. Exon expression profiling analyses revealed a part...
The recent discovery of meningeal lymphatic vessels (LVs) has raised interest in their possible involvement in neuropathological processes, yet little is known about their development or maintenance. We show here that meningeal LVs develop postnatally, appearing first around the foramina in the basal parts of the skull and spinal canal, sprouting a...
Lymphatic vessels are important for tissue fluid homeostasis, lipid absorption, and immune cell trafficking and are involved in the pathogenesis of several human diseases. The mechanisms by which the lymphatic vasculature network is formed, remodeled, and adapted to physiological and pathological challenges are controlled by an intricate balance of...
Using an in vivo reporter for lymphangiogenesis, a recent study in Nature from Olmeda et al. (2017) describes a new subset of melanomas that induce systemic pre-conditioning of distant organs for formation of tumor metastatic niches, and identifies the responsible factor as the pleiotropic cytokine midkine.
Chylous pleural effusion (chylothorax) frequently accompanies lymphatic vessel malformations and other conditions with lymphatic defects. Although retrograde flow of chyle from the thoracic duct is considered a potential mechanism underlying chylothorax in patients and mouse models, the path chyle takes to reach the thoracic cavity is unclear. Here...
Secondary lymphedema is a common post-cancer treatment complication but the pathomechanisms underlying the disease remain unclear. Using a mouse-tail lymphedema model, we found an increase in local and systemic levels of the lymphangiogenic factor VEGF-C, and identified CD68+ macrophages as a cellular source. Surprisingly, overexpression of VEGF-C...
Closed fluid circulatory systems developed in multicellular organisms in need to overcome the insufficient passive diffusion of oxygen and nutrients to tissues. When the cardiovascular system already functions in vertebrate embryos, the lymphatic vessel development adds another vascular system, which is responsible for tissue fluid homeostasis, imm...
BACKGROUND: Lymphoedema represents the cardinal manifestation of lymphatic dysfunction and is associated with expansion of the adipose tissue in the affected limb. In mice, high-fat diet (HFD)-induced obesity was associated with impaired collecting lymphatic vessel function, and adiposity aggravated surgery-induced lymphoedema in a mouse model. The...
Rationale: Vascular endothelial growth factor (VEGF) is the main driver of angiogenesis and vascular permeability via VEGF receptor 2 (VEGFR2), while lymphangiogenesis signals are transduced by VEGFC/D via VEGFR3. VEGFR3 also regulates sprouting angiogenesis and blood vessel growth, but to what extent VEGFR3 signaling controls blood vessel permeabi...
https://books.google.ch/books?hl=de&lr=&id=ANw-DgAAQBAJ&oi=fnd&pg=PA123&ots=Qh7fZv3o46&sig=wgnuj44EsarOuhr_DcI297boDus#v=onepage&q&f=false
Lymphatic vessels play important roles in fluid drainage and in immune responses, as well as in pathological processes including cancer progression and inflammation. While the molecular regulation of the earliest lymphatic vessel differentiation and development has been investigated in much detail, less is known about the control and timing of lymp...
Obesity comprises great risks for human health, contributing to the development of other diseases such as metabolic syndrome, type 2 diabetes and cardiovascular disease. Previously, obese patients were found to have elevated serum levels of VEGF-C, which correlated with worsening of lipid parameters. We recently identified that neutralization of VE...
Prox1 heterozygous mice have a defective lymphatic vasculature and develop late-onset obesity. Chyle abnormally leaks from those vessels, accumulates in the surrounding tissues, and causes an increase in adipose tissue. We characterized the lymphatics of Prox1 (+/-) mice to determine whether the extent of obesity correlated with the severity of lym...
Vascular endothelial growth factor (VEGF)-A is a well-known major chemoattractant driver of angiogenesis – the formation of new blood vessels from pre-existing ones. However, the repellent factors that fine-tune this angiogenic process remain poorly characterized. We investigated the expression and functional role of endothelial cellderived semapho...
The mammalian circulatory system comprises both the cardiovascular system and the lymphatic system. In contrast to the blood vascular circulation, the lymphatic system forms a unidirectional transit pathway from the extracellular space to the venous system. It actively regulates tissue fluid homeostasis, absorption of gastrointestinal lipids, and t...
Tumor-associated macrophages (TAMs) have been implicated in the promotion of breast cancer growth and metastasis, and a strong infiltration by TAMs has been associated with estrogen receptor-negative tumors and poor prognosis. However, the molecular mechanisms behind these observations are unclear. We investigated macrophage activation in response...
Lymphatic vessels play important roles in the pathogenesis of many conditions that have an increased prevalence in the elderly population. However, the effects of the aging process on the lymphatic system are still rel- atively unknown. We have applied non-invasive imaging and whole-mount staining techniques to assess the lym- phatic vessel functio...
The central nervous system (CNS) is considered an organ devoid of lymphatic vasculature. Yet, part of the cerebrospinal fluid (CSF) drains into the cervical lymph nodes (LNs). The mechanism of CSF entry into the LNs has been unclear. Here we report the surprising finding of a lymphatic vessel network in the dura mater of the mouse brain. We show th...
Tumor heterogeneity may broadly influence the activation of tumor-associated macrophages. We aimed to dissect how breast cancer cells of different molecular characteristics contribute to macrophage phenotype and function. Therefore, we performed whole transcriptome sequencing of human monocytes that were co-cultured with estrogen receptor positive...
Tumor heterogeneity may broadly influence the activation of tumor-associated macrophages. We aimed to dissect how breast cancer cells of different molecular characteristics contribute to macrophage phenotype and function. Therefore, we performed whole transcriptome sequencing of human monocytes that were co-cultured with estrogen receptor positive...
Objective
Elevated serum levels of the lymphangiogenic factors VEGF-C and -D have been observed in obese individuals but their relevance for the metabolic syndrome has remained unknown.
Methods
K14-VEGFR-3–Ig (sR3) mice that constitutively express soluble-VEGFR-3-Ig in the skin, scavenging VEGF-C and -D, and wildtype (WT) mice were fed either chow...
Lymphatic vessels are essential for fluid transport and tissue homeostasis. Recent discoveries identified several genes, including Prox1 and VEGF-C, which are required for the lymphatic vessel development in physiological conditions as well as under pathological conditions such as chronic inflammation and tumor progression. Lymphatic vessels show m...
Lymphatic vessels play an essential role in intestinal lipid uptake, and impairment of lymphatic vessel function leads to enhanced adipose tissue accumulation in patients with lymphedema and in genetic mouse models of lymphatic dysfunction. However, the effects of obesity on lymphatic function have been poorly studied. We investigated if and how ad...
Malignant tumors release growth factors such as VEGF-C to induce lymphatic vessel expansion (lymphangiogenesis) in primary tumors and in draining sentinel LNs, thereby promoting LN metastasis. Surprising recent evidence suggests that lymphatic vessels do not merely represent passive channels for tumor spread, but that they may actively promote tumo...
During development, the lymphatic and the blood vascular system form highly branched networks that show extensive architectural similarities with the peripheral nervous system. Increasing evidence suggests that the vascular and the nervous systems share signaling pathways to overcome common challenges such as guidance of growth and patterning. Sema...
Vascular endothelial growth factor-C (VEGF-C) and VEGF-D were identified as lymphangiogenic growth factors and later shown to promote tumor metastasis, but their effects on carcinogenesis are poorly known. We have here studied the effects of VEGF-C and VEGF-D on tumor development in the murine multi-step chemical carcinogenesis model of squamous ce...
Over the last 15 years, discovery of key growth factors and specific molecular markers for lymphatic vessels has enabled a new era of molecular research on the lymphatic vascular system. As a result, it has been found that lymphangiogenesis, the expansion of existing lymphatic vessels, plays an important role in tumor progression and in the control...
Over the last 15 years, discovery of key growth factors and specific molecular markers for lymphatic vessels has enabled a new era of molecular research on the lymphatic vascular system. As a result, it has been found that lymphangiogenesis, the expansion of existing lymphatic vessels, plays an important role in tumor progression and in the control...
Adhesion molecules play an important role in vascular biology because they mediate vascular stability, permeability, and leukocyte trafficking to and from tissues. Performing microarray analyses, we have recently identified activated leukocyte cell adhesion molecule (ALCAM) as an inflammation-induced gene in lymphatic endothelial cells (LECs). ALCA...
Lymphatic vasculature plays important roles in tissue fluid homeostasis maintenance and in the pathology of human diseases. Yet, the molecular mechanisms that control lymphatic vessel maturation remain largely unknown.
We analyzed the gene expression profiles of ex vivo isolated lymphatic endothelial cells to identify novel lymphatic vessel express...
To analyse the most common MEFV (Mediterranean fever gene) mutations and polymorphisms in an elderly population free of chronic inflammatory disease (n=164), and explore possible associations between hsCRP (high sensitive C-reactive protein) and RF (rheumatoid factor) levels with MEFV mutations and polymorphisms.
An elderly group free of chronic in...
Questions
Questions (4)
Hi Everyone,
I would like to generate a very simple ImageJ macro, which first measures the area in a user-selected region of interest (ROI) and then the fluorescence signal intensity within the same ROI that is adjusted by manual thresholding.
Attached is a PDF, which shows the steps in the macro, ROIs are indicated with yellow selection.
As the ROI selection and the thresholding needs to be done manually in every image by the user, I would need this macro to ask the user after an image is opened:
“Select your region of interest” (=> I guess this could even be skipped by starting the macro after the manual selection of the ROI.)
And then again the macro should stop to have the user set the threshold.
Any suggestions how can I incorporate these into such a macro?
Thanks very much for any suggestions,
Sinem
I would like to check in vivo insulin action, by assessing the IRS-1 and phospho-IRS-1, together with Akt and phospho Akt in adipose tissue after insulin administration. Any suggestions on protocols, and antibodies to purchase are welcome!
We would like to design FRET type of probes to detect the presence of alternatively spliced isoforms of certain genes. My question is regarding the optimal probe design. How long the probe should be? Would you use pure DNA probes or would you incorporate LNAs, and if yes which part of the probe (5', middle or 3')? Does it make sense to use a probe couple like FAM - Black Hole Quencher (BHQ) 1 and TAMRA - BHQ 2 for multiplexing?
I have cDNA from isolated murine macrophages (I have 4 samples from different mice) and I wanted to check the gene expression of 5 different genes. I obtained Ct values for these genes, however I am not sure how I should express these data since I am not comparing my data to any other condition (like control versus treated etc.). I thought of showing deltaCt values (difference between my target gene and my house keeping gene). Any ideas/ suggestions?
