Grant category: Research Grants in open competition

Grant category: Research Grants in open competition

Year: 2018

Geography: USA

Melanoma is the deadliest form of skin cancer with few treatment options to patients with advanced metastatic disease.

Melanoma metastasis to lymph nodes is associated with expression of the chemokine receptor CCR7, a member of the G protein-coupled receptors (GPCRs) superfamily that promote cell migration of immune cells. Classically, upon agonist stimulation, GPCRs at the cell membrane activate heterotrimeric G proteins, causing downstream signaling throughout the cell. In order to terminate G protein signaling, cells have devised a specialized desensitization mechanism that includes receptor phosphorylation by GPCR kinases and subsequent recruitment of β-arrestins (βarrs) to the phosphorylated receptors. The GPCR–βarrs interaction both blocks the G proteinbinding site and promotes receptor endocytosis.

However, we recently discovered that some GPCRs interact with G proteins and βarrs simultaneously to form GPCR–G protein–βarr ‘megaplexes’, which allows the receptor to continue to stimulate G protein signaling while being internalized into endosomes by βarrs. Our preliminary results suggest that CCR7 forms megaplexes and promotes G protein signaling from internalized compartments. Interestingly, endosomal signaling, in general, is highly involved in cell migration, and different proteins are trafficked between plasma membrane and endosomes during this process. Thus, the proposed project aims to investigate the involvement of endosomal CCR7 signaling in melanoma cell migration. Furthermore, using a combination of highly advanced cryo-electron tomography and APEX2 proteomics, we will visualize the mechanism of CCR7-mediated melanoma cell migration protein-by-protein. Such detailed mechanistic knowledge will assist in designing innovative therapeutics to treat metastatic malignant melanoma.

Grant category: Research Grants in open competition

Year: 2018

Geography: USA

Androgenetic alopecia (AGA, Male or Female Pattern Baldness) is the most common type of hair loss, affecting approximately 50% of men and 30% of women by the age of 50.

Current therapies, including pharmaceutical and surgical interventions, are either marginally effective or expensive with significant limitations. Over the last decade, breakthroughs made in the field of adult stem cells have laid the foundation for a cell-based approach to tissue and organ regeneration. Cell-based therapies will comprise a new wave of medical breakthroughs.

In this study we propose to produce human hair follicles from induced pluripotent stem (iPS) cells by directing these cells to form the two types of cells that are needed for human hair formation, namely the human hair follicle epidermal cells and the hair inductive dermal fibroblasts.

We will combine our hair biology and tissue-engineering expertise to generate early stage human hair follicles in culture that can be implanted into an animal model to grow into a mature hair. The long-term goals are to develop an innovative cell-based treatment for hair loss and an in vitro platform for testing hair growth compounds.

Grant category: Research Grants in open competition

Year: 2018

Geography: Netherlands

Psoriasis is highly prevalent and has a significant medical and socio-economic impact.

The prevailing dogma has been that abnormalities of the adaptive immune system were primary, but genetic studies have highlighted the importance of local skin-specific factors. We and others have identified epidermis-specific innate immunity genes, like beta-defensins and Late Cornified Envelope (LCE) genes, to be associated with disease development.

We recently made two exciting observations. First, deletion of LCE3B and LCE3C does not merely imply the loss of two genes but has a genomic effect that leads to a strong induction of the flanking LCE3A gene. Secondly, we found that LCE proteins, and LCE3A in particular, have broad-spectrum antimicrobial activity. We hypothesize that the LCE3B/C-del status affects the cutaneous host defense repertoire thereby shaping the skin microbiome. We aim to investigate the biology of LCE genes and to translate these findings to our understanding of psoriasis pathogenesis.

Key objectives are to:

1. assess the antimicrobial activity and specificity of all LCEs and their synergy with other antimicrobial proteins. This will be investigated by metagenomic approaches and classical in vitro microbiological assays, using recombinant and synthetic LCE proteins and peptides derived thereof
2. investigate LCE3B/C-del in isogenic 3D-skin equivalents in vitro generated from the immortalized human keratinocyte N/TERT cell line. Deletions of other LCE genes or their regulatory sequences will be made using CRISPR/Cas9 technology. Effects on epidermal biology relevant to psoriasis will be studied and include antimicrobial host defense, innate immune response and skin barrier function

Grant category: Research Grants in open competition

Year: 2018

Geography: USA

Basal cell carcinoma (BCC) is the world’s most common cancer and is defined by uncontrolled activation of the Hedgehog (Hh) signaling pathway.

Although previous studies have suggested that elevated Hh may be sufficient for BCC formation, mutations in the Notch pathway are also commonly observed. Furthermore, Notch-deficient mice are susceptible to forming BCCs, and our recent studies have shown that Notch can modulate tumor-drug response.

These studies seek to understand whether Notch affects multiple aspects of BCC tumorigenesis. Using a combination of animal studies and human BCC specimens, we will investigate how Notch modulates tumor progression and stem cell origin.

We will also model in mice a recent clinical trial, where Alzheimer’s patients treated with a Notch inhibitor reported increased incidence of BCC. We hypothesize that Notch may suppress tumorigenesis at multiple levels by controlling cell differentiation, apoptosis and turnover, similar to its function in normal skin and hair follicles.

These studies will ultimately build on the novel premise that BCCs may originate from a precursor lesion. Given that Notch mutations are the most commonly observed genetic aberrations in human skin, a deeper understanding of the tumor suppressive properties of this pathway is urgently needed.

Grant category: Research Grants in open competition

Year: 2018

Geography: Austria

Atopic dermatitis (AD), the most common chronic inflammatory skin disease, typically starts very early in life.

While many patients outgrow their disease, some develop chronic disease for the rest of their lives. Mechanisms responsible, however, are completely unknown, and no biomarker exists that can predict the course of the disease.

Thus, we want to compare skin from young adults that have outgrown their AD, with skin from patients with active disease (namely normal appearing AD under topical glucocorticoid treatment, which can be expected to flare up again after cessation of treatment, thus harbouring a “disease memory”).

Skin from healthy control subjects will serve as baseline comparators. Due to low immune cell numbers in this type of tissue, we want to use in vivo suction blistering of AD patients to obtain (i) skin resident immune cells and (ii) skin proteins. Suction blister fluid will be analysed with low cytometry and single cell RNAseq (for cells) as well as a proteomic multiplex assays (OLINK) for soluble proteins. The blister roof (i.e. the epidermis) will also be harvested, and keratinocytes will be stored in liquid nitrogen for functional experiments.

Results obtained from flow cytometry, single cell RNAseq and proteomic approaches will then be used for such functional in vitro experiments (e.g. co-culturing, skin equivalents, stimulation experiments) in future research projects.

Overall, we hope that the identification of cellular and/or molecular factors influencing the natural course of AD could possibly identify targets for novel therapeutic approaches in AD, that could induce long term remission – or even lead to a cure – of AD.

Grant category: Research Grants in open competition

Year: 2018

Geography: USA

My vision is to use metagenomics to better predict patient responses to immunotherapy and rationally design microbial adjuvant cocktails and engineered microbes to improve therapeutic outcomes.

However, a central question is the role of the local microbiota vs. systemic effects in potentiating these immunotherapeutics. In skin cancer, we have been studying how the skin microbiome affects predisposition and progression. Specific gut microbes have been implicated in the outcomes for immunotherapy response in melanoma skin cancer, supporting a role of systemic immune interactions via the gut in potentiating immunotherapy response.

However, because many aspects of cutaneous immunity are compartmentalized from systemic immune effects, we hypothesize that the skin microbiome could uniquely impact skin cancer outcomes during immunotherapy by modulating the cutaneous immune milieu.

Grant category: Research Grants in open competition

Year: 2017

Geography: Denmark

Recent studies of patients with psoriasis and type 2-diabetes have shown intriguing results: administration of glucagon-like peptide 1 (GLP-1) analogues was found to improve the severity of psoriasis. In another study, while not finding a significant beneficial effect of a GLP-1 analogue on disease score as compared to placebo, patients did report a significant decrease in their disease score as compared to baseline.

This has led a Denmark-based group to team up for further investigation of the effect of GLP-1 analogues on psoriasis, based on, among others, an assumption of a direct effect of GLP-1 analogues on the immune system – with the intention of clarifying if there may be a route to new treatment options for psoriatic patients.

More specifically, the team will investigate if the potential immunoregulatory effect of GLP-1R signalling on T cells in psoriatic plaques could be responsible for the patient-experienced alleviation of psoriasis. The team furthermore hypothesizes that vitamin D may play an important role in GLP-1R signaling and is important for alleviation of psoriasis as Vitamin D upregulates GLP-1R on T cells and low serum levels of vitamin D have been reported in psoriatic patients.

The majority of the experiments will be performed by Anna Kathrine Obelitz Rode under supervision of Martin Kongsbak-Wismann and Carsten Geisler, Department of Immunology and Microbiology, University of Copenhagen. Lone Skov, Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen will be co-supervisor on the project. The project will be performed in close collaboration with Charlotte Menné Bonefeld, Department of Immunology and Microbiology, University of Copenhagen.

The clinical studies in humans will be performed at the Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen in collaboration with Lone Skov.

Grant category: Research Grants in open competition

Year: 2017

Geography: USA

Atopic dermatitis (AD) is the most common inflammatory skin disease, with a prevalence in adults of 3% to 10% and a large unmet need for effective therapeutics.

Current clinical trials for AD patients assume a common disease mechanism. However, based on preliminary data, different therapeutics may be required to effectively treat different subsets of AD patients.

Biomarker-based studies show distinct clinical, and particularly molecular and cellular differences between different AD subpopulations such as African American, Chinese, and Indian AD patient populations.

However the characterization of the different and distinct clinical AD phenotypes is still at its very beginning. Indeed, there is high need of appropriate mechanistic studies to create a complete “molecular map” of AD across its different variants and hence to get a step closer for a personalized treatment approach.

Dr. Emma Guttman and her team at Icahn School of Medicine at the Mount Sinai Medical Centre, NY, USA, will seek a first time investigation to provide a systems biology approach for AD aiming to produce a molecular map of AD across its different subtypes.

The project integrates cellular and molecular biomarkers of lesional, but also non-lesional, skin and systemic inflammation to classify adult AD patients based on ethnic phenotypes, disease severity and age differences.

The proposal will set the stage for personalized therapy approach for AD based on skin and blood biomarkers and pathogenic variation of AD phenotypes related to severity, race/ethnicity and age.

Grant category: Research Grants in open competition

Year: 2017

Geography: USA

Despite decades of research, the root cause of psoriasis remains unknown and targeted approaches to cure psoriasis have to date been elusive.

Psoriasis is a physically and psychologically devastating skin disorder affecting more than 7.5 million Americans, with global prevalence ranging up to 4.6%. The disease causes profound physical, emotional, and social burdens translating into massive healthcare costs.

Theories of the biological mechanisms behind the disease range from genetic and epigenetic deviations to acquired defects involving a plethora of cellular and mechanistic culprits, including epidermal cell kinetics, endothelial-leukocyte interactions and perturbations in dermal nerve fibres, mast cells, lymphocytes and dendritic cells.

However, even if it is clear that a multiplicity of cellular pathways is involved, the primary events that initiate and drive disease remain unknown.

The team behind this study proposes a novel hypothesis that psoriasis is driven by immune-mediated dysregulation of stem cells within the epidermal and dermal compartments.

In the course of the study, the team will, for the first time, test the skin stem cell hypothesis of psoriasis causation with a highly-focused goal of defining the primary event(s) in lesion formation, thus providing a foundation for future pre-clinical targeted therapeutic approaches designed to actually cure psoriasis.

Grant category: Research Grants in open competition

Year: 2017

Geography: Denmark

The LEO Foundation has supported this project in appreciation of the fact that malignant melanoma has the highest death toll among skin cancer.

If and when melanoma is not diagnosed and treated early, the cancer may develop and spread to other parts of the body, where it becomes harder to treat and potentially fatal. Therefore, work to find new therapeutic targets for this particular aggressive cancer type is of extreme importance.

Professor Cecconi and his team have extensive and comprehensive expertise on the molecular ‘switch’ AMBRA1, believed to play a significant role in the body’s own defense against diseases such as cancer.

As an example, professor Cecconi was the first to identify the AMBRA1 gene and has been unraveling its multiple functions over the last 10 years. In particular, he has already demonstrated AMBRA1 playing a role as tumor suppressor in vivo, and preliminary data indicates the gene’s supposed role as a therapeutic target in cancer. Very intriguingly, most AMBRA1 mutations were found in melanoma patients.

The LEO Foundation finds this project to be innovative and commends its multidisciplinary approach, putting together different fields of research ranging from cell biology, mouse genetics, biophysics, computational biology and CRISPR/Cas9 technology.

Prof. Cecconi is member of the European Consortium Mel-Plex (Horizon 2020 Marie Curie Action), which includes several international researchers with the common aim of tackling melanoma – and these existing collaborations with melanoma experts will be of great importance in order to accomplish the project.