Establishing the keratinocyte stem cell basis for skin field cancerisation and squamous cell carcinoma
Grantee: Girish Patel, Honorary Senior Lecturer, Cardiff University
Amount: DKK 3,935,737
Grant category: Research Grants in open competition
Year: 2019
Geography: United Kingdom
Epithelial tissues, the environmental barriers of our bodies, are constantly exposed to cancer causing agents. As such carcinoma, the cancer of epithelial tissues, are the most common form of cancer accounting for 85% of all cancers and 78% of all cancer associated deaths.
Many carcinomas arise from a pre-cancerous transformation, known as intraepithelial neoplasia or field cancerisation (FC), within which multiple carcinoma can develop.
By studying skin FC in a mouse model of human papillomavirus 8 infection (K14-HPV8-CER), we have uncovered specific expansion of only the Lrig1 hair follicle junctional zone keratinocyte stem cells (HFJZKSC) driven by ΔNp63 expression, which is the basis for skin FC 1-3.
These findings raised two important fundamental questions:
- How does HPV8 induce Lrig1 KSC expansion? The background for this proposal and ongoing work (Leo Foundation grant 2017, LF17070).
- Are Lrig1 derived cells responsible for squamous cell carcinoma (SCC)? The basis for this Leo grant proposal.
The current Leo Foundation grant allowed us to identify E6 as the HPV8 protein responsible for Lrig1 KSC expansion through activation of the STAT3 intracellular signalling pathway.
Therefore, we are now positioned for a follow-on grant to determine whether Lrig1 derived cells are responsible for FC associated SCC. Herein we aim to:
1) confirm that Lrig1 HFJZKSC proliferation is responsible KSC expansion into the infundibulum and adjoining interfollicular epidermis
2) test the hypothesis that Lrig1 HFJZKSC progeny give rise to papilloma and SCC
3) determine whether STAT3 mediate HFJZKSC expansion occurs in human skin FC.
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.
Big Bang 2020-2021 – support for Denmark’s largest science conference
Grantee: Mikkel Bohm, Astra*, the national Centre for Learning in Science, Technology and Health in Denmark
Amount: DKK 2,000,000
Grant category: Education and Awareness Grants
Year: 2019
Geography: Denmark
Denmark’s largest science conference, the Big Bang Conference, has received DKK 2,000,000 for the period 2020-2021 from the LEO Foundation.
Big Bang is the largest Danish science conference and exhibition targeted all who teaches, facilitates or researches in the science and science fields – in primary and secondary schools and higher education.
The conference, held once a year, gathers more than 1,000 people for two involving and inspiring days with relevant keynote speakers, a humming exhibition atmosphere, involving workshops and novel ideas for the continued renewal of science education.
Future Leaders Symposium
Grantee: European Society for Dermatological Research
Amount: EUR 15,000
Grant category: Education and Awareness Grants
Year: 2019
Geography: Switzerland
By supporting investigative dermatology and skin research, the ESDR contirbutes to in-depth understanding of skin homeostasis and towards improving the health of patients suffering from skin and venereal disease, infectious diseases and immune-mediated and inflammatory disorders.
The LEO Foundation Award 2018 – Silver Award
Grantee: Dr. Tiffany Scharschmidt
Amount: DKK 500,000
Grant category: LEO Foundation Awards
Year: 2018
Geography: USA
The Silver Award went to Dr. Tiffany Scharschmidt from University of California San Francisco, USA, for her work on the skin microbiome and its interplay with the adaptie immune system.
Have a sneak peek into her research Video about Dr. Tiffany Scharschmidt
The LEO Foundation Award 2018 – Gold Award
Grantee: Dr. Hayato Takahashi
Amount: DKK 1,000,000
Grant category: LEO Foundation Awards
Year: 2018
Geography: Japan
The Gold Award went to Dr. Hayato Takahashi from Keio Unversity School of Medicine, Tokyo, Japan, to pursue his work on T cell-mediated autoimmune skin diseases.
Have a sneak peek into his research Video about Dr. Hayato Takahashi
Implementation of novel 3-bounce 2-pass ATR FTIR spectroscopy into the Skin Testing for Atopic dermatitis (STAR) study
Grantee: Dr Simon G. Danby, Independent Research Fellow, The University of Sheffield Medical School
Amount: DKK 390,506
Grant category: Research Grants in open competition
Year: 2018
Geography: United Kingdom
With this grant, the group led by Simon G. Danby seeks a potentially important technological addition to the ongoing A longitudinal investigation of skin barrier development from birth and the validation of early predictors of Atopic dermatitis (AD) risk: the skin testing for atopic dermatitis risk (STAR) trial (see Grants 2017).
This addition may prove valuable to the group’s envisioned paradigm shift – from management of established AD to primary prevention of the condition.
More specifically, the group will include enhanced ATR-FTIR spectroscopy to quantify biomarkers of skin barrier condition and AD severity in newborns. While existing spectroscopy works in adults and children, its sensitivity has been proven unsatisfactory when measuring newborns.
Working with the equipment manufacturer, the group has developed a solution that increases sensitivity 6-fold. This increase can help better prediction of the risk of AD in the newborn and thus enable targeted emollient intervention right from birth – potentially leading to a reduction of the incidence of the condition as increasing evidence suggests that topical emollient therapy can prevent the initial onset of AD by 50%.
AD is a very common chronic inflammatory skin condition affecting around 20% of children worldwide. The disease often heralds development of allergic diseases such as food allergy, asthma, and allergic rhinitis.
Project Group
Prof. Michael J. Cork and Mr J. Chittock, The University of Sheffield, United Kingdom
Dame Prof. Tina Lavender and Dr Alison Cooke, The University of Manchester, United Kingdom
GWA studies on common dermatological diseases
Grantee: Professor Gregor B. Jemec, Department of Dermatology, Zealand University Hospital, Roskilde, and Assoc. Professor Ole B. V. Pedersen, Department of Clinical Immunology, Næstved Hospital
Amount: DKK 5,770,000
Grant category: Research Grants in open competition
Year: 2018
Geography: Denmark
In this study, the group led by Professor Gregor Jemec of Roskilde Hospital has set out to identify new genes for the development of a long line of common dermatological conditions, including deep skin infections, warts, fungal infections, and eczema.
Many of these common skin diseases are still poorly understood and the treatments often insufficient. A study of the genetics of these disorders will help increase the understanding of the pathogenic mechanisms. The study will have its origin in Denmark and be based on unique national biobanks, national registries, and with extensive genetic analyses done in collaboration with deCODE Genetics, Iceland.
This is possible due to the growing number of Danish large-scale biobanks as well as biobank based scientific studies suited for further genetic studies. The largest genetic study in Denmark is the Danish Blood Donor Study (DBDS) in which the genome wide association (GWA) arrays have been analysed on 110,000 research participants.
In addition to this cohort, Jemec’s group is currently pursuing genetic testing on the Copenhagen Hospital Biobank (CHB) that includes samples from around 350,000 patients. Both of these biobanks have established a collaboration with deCODE Genetics, Iceland – one of the leading genetic research centers in the world.
Project Group
Henrik Ullum, Professor, Department of Clinical Immunology, Rigshospitalet
Søren Brunak, Professor, Center for Protein Research (CPR), Copenhagen University
Simon Francis Thomsen, Professor, Department of Dermatology, Bispebjerg Hospital
Claus Zachariae, Professor, Department of Dermatology, Gentofte Hospital
International affiliations
Ingileif Jonsdottir, Professor, deCODE Genetics, Iceland
Errol Prens, Professor, Department of Dermatology, Erasmus University, Rotterdam, Netherlands
Christos Zouboulis, Professor, Department of Dermatology, Brandenburg Medical School Theodor Fontane, Dessau, Germany
Fully Synthetic Lincosamides to Combat Multidrug-Resistant Skin Infections
Grantee: Prof. Dr. Andrew G. Myers, Amory Houghton Professor of Chemistry Harvard University, Cambridge, MA
Amount: DKK 3,108,110
Grant category: Research Grants in open competition
Year: 2018
Geography: USA
Many common skin infections are caused by the Gram-positive bacterial species Staphylococcus aureus and Streptococcus pyogenes. The infections lead to conditions ranging in severity from minor folliculitis to life threatening skin reactions. If not managed successfully, they may escalate into lethal systemic infections.
Commonly, these diseases are treated with clindamycin, a prototypical member of the wide-ranging so-called lincosamide antibiotic class. Its clinical importance is underlined by the World Health Organization’s listing of it as an essential medicine. In the past decades, however, prevalence of in particular lincosamide resistant Staphylococci and Streptococci has risen sharply. The rise threatens to diminish clindamycin’s usability in the future, even render it obsolete.
In the course of this project, the team led by Andrew G. Myers of Havard University, will seek to address this growing unmet medical need by synthetic discovery efforts focused on the lincosamide class.
The team’s preliminary results indicate that new lincosamides uncovered in this fashion are able to address the contemporary resistance threats: Many of the compounds designed, synthesised, and evaluated by the team to date have shown themselves active against multidrug-resistant clinical isolates of Staphylococci and Streptococci, and at the same time they demonstrate favourable pharmacokinetic and safety profiles.
The team expects that it can uncover new candidates displaying expanded spectra of action against MDR and Gram-negative bacteria. The expected results can then be used to advance refined lead candidates capable of demonstrating efficacy in in vivo murine models of skin infection, and thus yield substantial promise for further clinical development of actual treatments.
Project group
Dr. Amarnath Pisipati, Postdoctoral microbiologist
Matthew J. Mitcheltree, PhD student, chemistry
Ioana Moga, PhD student, chemistry
Katherine J. Silvestre, PhD student, chemistry
International affiliation
The Institut Pasteur, Annecy, France – International Course on Antibiotics and Resistance (ICARe), Organizing Committee, Core Faculty
In vivo model of human melanoma using a novel crest chimera system
Grantee: Dr. Rudolf Jaenisch, Member, Whitehead Institute and Professor, Department of Biology, Massachusetts Institute of Technology, MA
Amount: DKK 2,476,836
Grant category: Research Grants in open competition
Year: 2018
Geography: USA
Two major challenges when using mouse models to model human cancers such as melanoma are that the human tumor cells transplanted to mice 1) represent the end-stage of the disease and 2) that the host animals are usually immunocompromised.
Thus, these models fail to actually show development of the disease and they fail to display the ongoing interaction between melanoma cells and the immune system as the disease progresses.
To curb these two shortcomings, the team led by Rudolf Jaenisch of Massachusetts Institute of Technology, has set out to create an experimental model system that will make it possible to study initiation, progression, and manifestation of human melanoma in immune competent host animals.
Their basis is generation of human-mouse neural crest chimeras – where mice embryos are introduced with human neural crest cells carrying the genetic dispositions alleged to lead to development of the particular cancer – and their goal is a model that has the potential to show how melanoma cells evade the immune system.
Given a positive outcome, this innovative project can help devise strategies to improve the effectiveness of current immunotherapies, to test novel immunotherapies, and to identify novel targets in melanoma treatment.
Project group
Malkiel Cohen, Postdoctoral researcher
Kristin Andrykovich, Graduate Assistant