The LEO Foundation Award 2019 – Region Americas

Grantee: Maksim Plikus

Amount: USD 100,000

Grant category: LEO Foundation Awards

Year: 2019

Geography: USA

Maksim Plikus is Associate Professor at the Department of Developmental and Cell Biology, School of Biological Sciences, University of California, Irvine, USA

He receives 100,000 USD for his research in skin stem cells and regeneration.

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Elucidating the origins of melanoma

Grantee: A. Hunter Shain

Amount: DKK 2,500,000

Grant category: Research grants in open competition

Year: 2019

Geography: USA

The overarching goal of this grant is to better understand the origins of melanomas that appear suddenly, or de novo.

Approximately 70% of melanomas appear in this way, while the remainder grow out of preexisting nevi. Nevi can be monitored and prophylactically removed if they show signs of change, but melanomas that arise de novo are impossible to foresee. It is therefore of utmost importance to understand the origins of melanomas that appear de novo in order to develop biomarkers to predict their emergence.

We previously sequenced melanomas adjacent to nevi, revealing two classes of mutations – initiating mutations (emerging in nevi) and progression mutations (emerging in melanoma). Here, we hypothesize that progression mutations can precede initiating mutations. In this scenario, a melanocyte silently accumulates progression-associated mutations, followed by an initiating mutation so that the ensuing neoplasm ‘skips’ the precursor stages, manifesting directly as a melanoma.

If validated, this hypothesis would explain how de novo melanomas evolve. Here, we will genotype individual melanocytes from healthy human skin to test whether morphologically normal melanocytes can harbour progression mutations. Towards this goal, we have developed innovative solutions to establish high-quality genotyping calls from individual cells. In our preliminary data, we genotyped 17 melanocytes collected from healthy skin, and pathogenic mutations were surprisingly common, supporting our hypothesis. We will extend these studies to fully delineate the spectrum of cancer-associated mutations in melanocytes from healthy skin.

Overall, completion of these studies will reveal the origins of melanomas that do not pass through a precursor stage – a longstanding goal in the skin research community.

A multi-pronged approach to decipher the role of melanosomal transporters in human pigmentation

Grantee: David M Sabatini, Professor of Biology, Whitehead Institute of Biomedical Research

Amount: DKK 2,666,588

Grant category: Research grants in open competition

Year: 2019

Geography: USA

Dozens of genes are known to be involved in human pigmentation. Many of these genes encode proteins with well-understood functions, such as in melanocyte development, melanin biosynthesis, and the biogenesis and trafficking of specialized melanin-containing organelles called melanosomes.

Yet, we do not know the molecular function of a class of pigmentation genes encoding putative transport proteins that localize to the melanosome. Identifying their substrates would represent a significant advance in our understanding of how melanin synthesis is regulated and how variants in these genes result in differences in human pigmentation.

Based on a method we developed to rapidly and specifically isolate melanosomes, termed MelanoIP, we can capture melanosomes in minute time-scales such that their labile metabolic contents are preserved for quantitative analysis.

Using this technology, we have performed a comparative study of melanosomal metabolites from cells with several pigment genes disrupted, including the putative melanosomal transporter encoding genes Slc45a2, Oca2, and Mfsd12, which has revealed potential substrates. In this proposal, we will define the substrates of these transporters using MelanoIP, metabolite profiling, and organellar uptake screens.

We will also perform follow-up biochemical analysis of each transporter and its naturally occurring genetic variants. Our unique combination of rigorous approaches will inform our understanding of how melanosomal transporters regulate melanin synthesis, and uncover the molecular basis of how mutations in these melanosomaltransport genes lead to human pigment variation.

Knowledge gained from this study will inform the development of interventions for modulating pigmentation and treating pigmentation pathologies.

Role of Skin Stem Cells in Psoriasis and Atopic Dermatitis

Grantee: George Murphy, Professor, Brigham & Women’s Hospital, Boston

Amount: DKK 3,988,427

Grant category: Research grants in open competition

Year: 2019

Geography: USA

This two-year proposal is based on the hypothesis that skin stem cells are critically involved in the pathogenesis of psoriasis and atopic dermatitis.

In previous work, the three principal investigators have identified a cytokeratin 15-expressing stem cell niche at the tips of epidermal rete ridges, discovered immunomodulatory dermal mesenchymal stem cells, and defined an epigenetic mark that regulates skin stem cell behavior.

During the past year that was funded by the LEO Foundation, we have provided data that supports epidermal stem cell participation in human and experimental psoriasis and begun to probe the genetic and epigenetic underpinnings of this phenomenon.

We now propose to advance these findings to determine mechanistic commonalities in stem cell behavior that may unify the pathogenesis of psoriasis and atopic dermatitis. Specifically, the proposal focuses on epidermal and dermal stem cells in the context of innovative experimental models, human biospecimens to test relevance, and epigenetic modifiers that may be transformative in normalizing stem cell aberrations responsible for the initiation and propagation of these two prevalent, pernicious, and potentially preventable skin diseases.