The research within our LUMC departments is conducted within departmental research programmes. The research programme below is embedded within the department of Dermatology.
- Research programme: Dermatology-oncology
- Department: Dermatology
- Programme leader: Prof. Dr. M.H. Vermeer
- Principal investigators: Dr. C.P. Tensen, Dr. K. Quint, Prof. Dr. R. Willemze, Dr. R. van Doorn, Dr. N.A. Gruis, Dr. N.A. Kukutsch, Dr. J.N. Bouwes Bavinck, Dr. A. el Ghalbzouri
- Biomedical research profile: Cancer Pathogenesis and Therapy
Aim and focus
Dermato-oncology is the main research theme at the department of dermatology and focusses on three topics: 1. cutaneous lymphoma 2. (familial) melanoma; and 3. keratinocyte carcinoma, particularly in organ-transplant recipients. The department of Dermatology is recognized as tertiary referral center for all three patient groups. Dedicated clinics for all patient groups are instituted that serve a dual purpose namely: ensuring optimal patient care, (including access to clinical trials), and systematic collection of clinical data and patient samples. Basic, translational and clinical research is coordinated in collaboration by clinicians and basic scientists using the clinical information and clinically annotated material generated by these specialized clinics.
Central themes within our research are characterization of clinical relevant patient subgroups and clinicopathological entities, identification of (epi)genetic alterations and environmental factors involved in the development and progression of these different types of skin cancer and interaction of tumor cells with the immune system.
Methods employed include clinicopathologic studies, epidemiological studies, microarray and next generation sequencing based technology, and model systems among which cell cultures of patient derived primary tumor cells and cell lines, the 3D-reconstructed human skin models and mouse models.
The ultimate goal is to identify and validate new diagnostic and prognostic markers and new targets for therapeutic and preventive strategies, and translation of these findings into daily clinical practice.
A. Cutaneous lymphomas
The Department of Dermatology LUMC is an (inter)national referral center for cutaneous lymphomas and homes the registry of the Dutch Cutaneous Lymphoma group (DCLG). The DCLG registry is unique in the world for the number of included patients (>4000), standardized therapy and long term follow-up. Clinical care is performed in close collaboration with the department of radiation oncology, haematology and pathology including weekly meeting with the pathology department and radiation oncology every two weeks. Research is performed with these partners supplemented with the departments of clinical oncology, cell biology and human genetics within the framework of the Cancer Pathogenesis and Therapy (CPT) research group. Coordination of trial development, grant proposals, and progress of PhD’s is ensured by monthly meetings of the Cutaneous Lymphoma expertice Center (CLEC).
Our research group was the first to recognize that primary cutaneous lymphomas, i.e. malignant lymphomas presenting in the skin without concurrent extracutaneous disease, have a completely different clinical behaviour and prognosis, as compared to histologically similar systemic lymphomas involving the skin secondarily, and therefore require a different type of treatment. In the last two decades our group described several new types of primary cutaneous T-cell lymphomas (CTCL) and primary cutaneous B-cell lymphomas (CBCL), including the spectrum of primary cutaneous CD30-positive lymphoproliferative disorders (cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis), folliculotropic mycosis fungoides (MF), aggressive epidermotropic CD8+ CTCL with a cytotoxic phenotype, CD4+ small pleomorphic CTCL, primary cutaneous follicle center cell lymphoma, primary cutaneous large B-cell lymphoma of the leg and others.
Capitalizing on the extensive tissue collection in the archives of the DCLG combined with long-term clinical follow-up data present within the DCLG database, we formulated and validated diagnostic criteria, including new criteria for Sézary syndrome (SzS), and developed clinical guidelines to ensure optimal management and treatment of the different types of cutaneous lymphoma. The advances in classification combined with large cliniopathological studies provided clinicians with detailed information on clinical course, response to therapy and prognosis. Results from these studies have now been incorporated in the recently published WHO-EORTC classification of cutaneous lymphomas (2005) and the 2016 revision of the WHO classification for malignant lymphomas, and international guidelines for the diagnosis and management of these diseases by the International Society for Cutaneous Lymphoma (ISCL) and EORTC (2008 and 2017).
Studies of our group using well-annotated clinical samples for micro-array based studies (gene expression profiling, comparative genomic hybridization, microRNA profiling) demonstrated clear-cut differences in molecular alterations between different types of cutaneous lymphomas and, identified (potential) diagnostic and prognostic markers as well as therapeutic targets. Currently more refined analyses (using next generation transcriptome and whole genome sequence analysis) are carried out in collaboration with groups in New York (USA), London (UK), Greifswald (Ger), Milan and Pavia (It). These studies have not only resulted in novel diagnostic and prognostic markers but also identified critical signalling pathways involved in the pathogenesis of Sézary syndrome (SzS) and MF.
To enable translational studies on larger groups of cutaneous lymphoma patients and patients treated within clinical trials we are heading an EORTC consortium for SzS, and lead the biobanking and translational research the EORTC cutaneous lymphoma task force (CLTF) http://www.eortc.org/, and the world wide Cutaneous Lymphoma International Consortium (CLIC) http://www.clicstudy.org/, and the EORTC cutaneous lymphoma working group.
Clarifying the genetics of melanoma susceptibility has been a core research activity for the department of dermatology. Our studies have resulted in the identification of a founder mutation in the cell cycle regulator gene CDKN2A (p16-Leiden mutation) in familial melanoma patients . Genotype-phenotype correlation in carriers of the p16-Leiden mutation showed a highly variable risk to develop melanoma, suggesting a role for other genetic and environmental factors. In collaboration with international partners in the melanoma genetics consortium GenoMEL genome-wide association studies on large sporadic melanoma case-control cohorts have revealed susceptibility loci for melanoma occurring in the general population. These susceptibility loci are primarily related to genes with a functional role in pigmentation, nevus development and telomere maintenance. Our current studies are aimed at identifying the genetic basis of familial melanoma in cases not explained by any of the known gene mutations using whole exome and genome sequencing of families. In these studies, performed with the department of clinical genetics, have revealed novel candidate genes. Validation of these genes in additional cohorts and functional analysis of genetic variants in melanoma development are ongoing. In addition to genetic alterations, the role of DNA methylation alterations in the development and progression of melanoma is analysed on a genome-wide scale. For the analysis of genetic and also immunological factors in the invasive growth of melanoma we make use of 3D in vitro melanoma models generated at our research laboratory. The department has the largest pigmented lesion clinic in The Netherlands and serves as a tertiary referral center for (familial) melanoma. Current clinical research, aimed at optimizing the management of patients at high risk of melanoma, is focused on genetic and environmental risk factors risk and the use of new diagnostic devices (dermoscopy and Raman spectroscopy).
C. Keratinocyte carcinoma
The aim of this research line is to gain an understanding of oncogenic changes involved in the formation of keratinocyte carcinomas, in particular in the clinically important group of organ-transplant recipients. The ultimate goal is to identify targets for therapeutic or preventive intervention. Epidemiological studies are performed in close collaboration with the groups mentioned in chapter 3. In an international multicenter study pain was identified as an important patient-reported diagnostic factor for cutaneous squamous-cell carcinoma (SCC). Together with scientists in Germany, France, UK, Italy and Australia an important role of human-papillomavirus infection for the development of SCC was established, which opens the door for future prevention with HPV vaccination. Prevalence and risk factors for SCC metastases are also studied.
In vitro reconstructed human skin models of human actinic keratosis and squamous cell carcinoma are developed to test targeted anti-tumor medication without ethical restrictions and with direct human relevance, thus superseding current animal models. A specific aim of this research line is to further develop these in-vitro human skin models for immunotherapeutic research in collaboration with medical oncology that will contribute to a better understanding of the interaction of skin malignancies with the immune system.
At present this model is being optimized to investigate the interaction of cancer-associated-fibroblast (CAFs) with tumor cells and other cells in the tumour microenvironment (TME). This line is aided by specific expertise of the department of gastroenterology-hepatology on CAF mediated interactions, especially in regards to the TGF-β signalling pathway and crosstalk with immune cells. We aim to develop a next generation of immunological based 3D skin tumor systems that will be implemented by all CPT partners.
In addition, since 2015 we collaborate with the companies Micronit and Fluigent to develop an “organ (skin)-on-a-chip” system with the aim to better understand the interaction of different cells (e.g. T cells, Macrophages) in a flow system that will be a valuable addition to our existing 3D-disease models and could also contribute to the generation of human (pre-) clinical trials-on-chips and personalized drugs.
Position in international context
A. Cutaneous Lymphomas
Our department is one of the few dermatology departments in the world that has a large cutaneous lymphoma clinic with access to all available treatment options combined with clinical, translational and basic research. In an international context the local research infrastructure with collaborations with the departments of pathology, haematology, clinical oncology, clinical genetics is exceptional.
Multiple international collaborative studies have been in initiated by our group with members of the EORTC cutaneous lymphoma working group (CLWG) including clinicopathological studies aimed at characterization of different types of cutaneous lymphoma (ie Sezary syndrome, subcutaneous panniculitis like T-cell lymphoma) and molecular studies focussing on specific genetic lesions in cutaneous lymphoma subtypes (copy number alterations and mutations in Sézary syndrome, CDKN2A deletions in primary cutaneous large B-cell lymphoma). We participate in international EORTC sponsored and pharma initiated trials including current trials of anti CD148k antibodies, antiCCR4 antibodies and resminostat.
We currently lead an EORTC consortium that focusses on diagnostic and prognostic markers in Sézary syndrome and lead translational research performed within the framework of an international clinical trial on extracorporeal photopheresis (PROMPT study). In addition Prof MH Vermeer coordinates biobanking and translational research of the EORTC cutaneous lymphoma group and the Cutaneous Lymphoma International Consortium (CLIC) while Prof Willemze leads the histology group of CLIC. Our department currently participates in three international clinical trials and Prof MH Vermeer participates in two advisory/safety boards.
Studies from our group have been critical in the development of the WHO classification for cutaneous lymphomas and formulating clinical guidelines for management of these diseases. Prof Willemze has been on the advisory board of the WHO and is currently editor of the cutaneous lymphoma chapters for the 4th edition of the WHO classification for Skin Tumours. Prof Vermeer is member of the board of the EORTC and president of the ISCL, and organized the three yearly meeting of the ISCL in New York in 2016.
The nature of the studies to identify and validate melanoma susceptibility genes and melanoma progression genes entails the analysis of large cohorts of rare patient samples and therefore requires international cooperation. The Leiden melanoma group has done so successfully for over 20 years now. For basic research and clinical implementation of research findings the LUMC melanoma group participates in several European global consortia. The most important is GenoMEL (http://www.genomel.org/). This consortium with members in Leeds, Cambridge, Heidelberg, Essen, Lund, Paris, Genoa, Valencia, Riga, Oslo, Boston, Brisbane, Boston, Tampa and Philadelphia is the world leader in familial melanoma studies. It is led by prof. J Newton Bishop (Leeds University) and dr N Gruis from our department serves as vice chair. Many genetic epidemiological studies have been performed in collaboration with partners of GenoMEL evidenced by 8 research articles published in Nature Genetics. Achievements include the identification of the 24 melanoma susceptibility loci by genome-wide association studies. Optimization of clinical genetic testing and melanoma risk assessment is facilitated by active participation in this network. The interests of the research groups that form the GenoMEL consortium have broadened to the genetic factors that determine melanoma behaviour and survival, leading to the formation of the BioGenoMEL consortium. This consortium is also chaired by prof. J Newton Bishop with dr R. van Doorn from our department serving as vice chair. The research collaborations of the GenoMEL/BioGenoMEL members have been strengthened by a Horizon 2020 EU Marie Sklodowska-Curie Innovative Training Network grant to the Leeds, Leiden, Cambridge, Lund, Oslo, Essen and Zurich groups. The two international PhD students trained in Leiden will have secondments to perform collaborative studies at the Sanger Institute (dr. David Adams) and at the GenomeScan, a SME providing genomics services in Leiden (prof. Bart Janssen). Since 2014 our department is partner in a TRANSCAN Joint Transnational call, led by prof. R Kumar (DKFZ, Heidelberg University) with participating groups from Leiden, Ancona, Bergen and Riga. The collaborative studies of this TRANSCAN network are aimed at finding genetic markers involved in melanoma metastasis. In addition, for epigenomic analysis of melanoma metastatic behaviour, for which dr R van Doorn received a young investigator award from the US-based Melanoma Research Alliance, collaborative studies were conducted with Leuven (prof. Van den Oord), Amsterdam (prof. D Peeper) and Maastricht (prof. M van Engeland). Our department has been a strong partner in these international consortia primarily due to its capacity to systematically collect unique well-annotated patient material and secondly due to its expertise in genomics and functional genetic validation of gene variants. Our role in the development of national clinical melanoma guidelines and the application of novel research insights into clinical practice is facilitated by our position in these international consortia.
C. Keratinocyte carcinomas
As one of the leading centers, epidemiological studies are performed in close collaboration with the SCOPE (Skin Care in Organ transplant Patients Europe); ITSCC (International Transplant Skin Cancer Collaborative); KeraCon (Keratinocyte carcinoma Consortium) and EPI-HPV-UV-CA groups.
SCOPE was established in 2002 in Berlin and consists of leading physicians and scientists who are involved in specialized care of skin problems in transplant recipients. SCOPE congresses are organized each year in different European cities. Not much later the American sister organization, ITSCC was founded. Our department has a leading role in organizing research in the SCOPE group. These studies identified pain as an important patient-reported symptom for SCC (Bouwes Bavinck 2014), described abundant mRNA expression for PGE2, TNFA, and POMC in painful SCC lesions (Frauenfelder 2017), and identified increased overall mortality risk if patients develop painful SCC (Oh 2017).
The Leiden human skin model group has a long standing collaboration with the cosmetic company CHANEL Parfum Beauté. The research that has been performed in the last 6 years is mainly focussed on developing a new anti-aging concept on molecular and cellular level. In the first PhD program funded by this sponsor we discovered a niche in the anti-aging field, patented biomarkers and developed compounds that are able to revert gene-signatures of aged fibroblasts. In addition, we gained knowledge on how different fibroblast lineages in the dermis affect extracellular matrix formation, melanogenesis, barrier formation, dermal stretching and cancer invasion. At present we focus on the use of these compounds for therapeutic oncologic purposes. Within the framework of this collaboration we developed 2D and 3D platform for compound-screenings and initiated a collaboration with prof J Grillari (Christian Doppler Laboratory on Biotechnology of Skin Aging, Department of Biotechnology and BOKU - University of Natural Resources and Life Sciences (Vienna)), to use his patented SNEV-technology to generate cell lines from specific fibroblasts lineages. This technology will also be used to investigate therapeutic manipulation of cancer associated fibloblasts and inhibit fibroblasts senescence in order to generate skin models that represent different states of the senescence pathway.
Content / highlights / achievements
More than 30 awarded grants from the Dutch Cancer Society (NKB/KWF; n=9), the EU (n=5), NWO/ZonMW (n=7), STW (n=3), NIH (n=1), BBMRI and pharmaceutical companies (n=7) in the period 20010-17
A. Cutaneous Lymphomas
Clinicopathologic studies from our group described several new types of CTCL and CBCL that have now been incorporated in the recently published WHO-EORTC classification of cutaneous lymphomas (2005) and the 2016 revision of the WHO classification for malignant lymphomas. We formulated international guidelines for the diagnosis and management of these diseases by the International Society for Cutaneous Lymphoma (ISCL) and EORTC (2008 and 2017). These advances in classification that provide clinicians with detailed information on clinical course, response to therapy and prognosis combined with clinical guidelines represent major advances in the clinical management of cutaneous lymphomas.
Using well annotated clinical samples with long-term clinical follow-up we performed immunohistochemical studies and micro-array based studies (gene expression profiling, comparative genomic hybridization, microRNA profiling) that demonstrated clear-cut differences between different types of CTCL and CBCL. These studies further supported the classification for cutaneous lymphoma and provided new diagnostic and prognostic markers as well as therapeutic targets. Studies performed on cutaneous large B-cell lymphoma were financed by Dutch Cancer Society and Clinical Fellowship from the Dutch Health Council.
Leading an international multicentre study we described recurrent copy number alterations in SzS followed by more refined analyses (using next generation transcriptome and whole genome sequence analysis) carried out in collaboration with groups in New York (USA), London (UK), Greifswald (Ger), Milan and Pavia (It). Combined these studies identified critical signalling pathways involved in the pathogenesis of Sézary syndrome (SzS) including STAT3.
Studies in SzS focussed on STAT3 signalling as therapeutic target (financed by a VIDI grant) and diagnostic criteria (financed by Dutch Cancer Society). The relative large and well defined patient cohort derived from this project was instrumental in characterizing the mutational background which we reported in Nature Genet. Further characterization of structural chromosomal alterations is currently done with support from the Dutch Cancer Society. Based on recurrent mutations found in epigenetic genes we analysed micro-RNA, DNA methylation profiles and initiated studies on histone modifications using ChIPSeqQ
To enable translational studies on larger groups of cutaneous lymphoma patients and patients treated within clinical trials we are heading an EORTC consortium for SzS, and lead the biobanking and translational research the EORTC cutaneous lymphoma working group (CLTF) http://www.eortc.org/, and the world wide Cutaneous Lymphoma International Consortium (CLIC) http://www.clicstudy.org/, and the EORTC cutaneous lymphoma working group.
Honours and Awards
Prof MH Vermeer:
- 2007 LUMC Marie Parijs Prize
- 2008 Member of the board EORTC
- 2015 President International Society for Cutaneous Lymphoma (ISCL)
- 2015 Organizer of the European Society of Dermatological Research meeting in Rotterdam
- 2016 ISCL Leadership Award
- 2016 Co-Organizer ISCL meeting NewYork.
- 2017 Eduard Arning Gedachtnis Lesung Hamburg
Prof R Willemze:
- 2014: Neil Smith Lecture, EORTC CLTF meeting
- 2015: Ultmann memorial lecture, ICML, Lugano
- 2015: Annual Lecture ISCL; Vancouver
- 2015: Certificate of Appreciation of the International League of Dermatological Societies
- 2016: Life Time Award International Society of Cutaneous Lymphomas
The melanoma research group of the department of dermatology has published over 100 research articles since 1986 with identification of CDKN2A as a melanoma-predisposition gene being one of its achievements. Participation in the GenoMEL international consortium has resulted in delineation of the major melanoma susceptibility gene variants reported in 8 Nature Genetics publications. Research at our department has been made possible by funding and awards from EU (FP6-HEALTH, FP7-Eurocan, Marie Curie, Transcan), KWF (project, young investigator), Melanoma Research Alliance (young investigator), Netherlands Enterpirse Agency (Photonics), amounting to 1.5 million euro in the previous 5 years. New sequencing methodologies have opened new avenues for the study of melanoma susceptibility and progression genes. Facilities for performing genomics studies are strong at LUMC and collaboration with research groups at the department of Molecular Cell Biology (dr AG Jochemsen) have increased our joint capability to examine the function of identified gene variants. Research projects over the past 5 years include whole genome and exome sequence analysis for identification of melanoma-predisposition genes in familial melanoma cases, functional genetic analysis of novel candidate melanoma-predisposition genes, development of gene panel sequencing in clinical genetic DNA testing of patients with familial melanoma (with department of clinical genetics), genome-wide DNA methylation profiling to identify biomarkers for melanoma metastatic behaviour, application of Raman spectroscopy in the diagnosis of early stage melanoma and defining clinical characteristics of patients at increased risk of developing melanoma. Of these projects the results from whole genome sequencing of DNA from familial melanoma patients and from functional genetic analysis of several candidate genes emerged from whole exome sequence analysis appear to be the most promising. Identification of novel melanoma susceptibility genes would create an opportunity for subsequent epidemiological and gene-environment interaction studies, and for implementation of genetic testing in the clinic. Subsequent studies would also include those on prevention of other tumor types in germline mutation carriers, such as pancreas screening with MRI for CDKN2A mutation carriers.
Building on our clinical expertise and research we are the leading center in the education for PhD students, medical residents, interns and students and guideline development for melanocytic lesions and melanoma in the Netherlands. Dr N Kukutsch serves in the board of the Stichting Melanoom that developed the Skin Monitor App that was selected as best Health App Award in 2012.
Honors and awards
- Dr R van Doorn - 2010 Melanoma Research Alliance Young Investigator Award
- Dr NA Gruis - 2003 LUMC Marie Parijs Prize
C. Keratinocyte carcinomasWe investigated the influence of infection with human papillomaviruses of the beta genus (betaPV) on the development of SCC. In organ transplant recipients from the LUMC, HPV antibody responses were analysed between 1 year before and 1 year after transplantation in 445 patients. Patients who were betaPV seropositive around the time of transplantation had an almost 3-fold increased risk of developing SCC during the 22-year follow-up period. We have found that sensation of pain in cutaneous tumors is a powerful patient-reported warning signal for SCC in organ transplant recipients. These patients also have an increased overall mortality risk.
We have developed human skin models for inflammatory skin diseases (e.g. eczema, blister diseases), cutaneous malignancies (e.g. SCC, melanoma) and skin processes (e.g. skin aging, pigmentation, wound healing, bacterial infections), that are used for screening purposes as alternatives to animal testing. In 2008 we have initiated a study in which Vvalidatedion of the Leiden human skin model according to the ECVAM (EU) guidelines for skin corrosion and irritation. These skin models are perfectly suited for safety testing of compounds from the cosmetic, chemical and pharmaceutical industry. For this purpose a spin-off company (Biomimiq) has been launched at the Bioscience-park that offer services to the cosmetic, food, chemical and pharmaceutical industry and co-development activities. In line with this we have also deliverd the first proof on concept of a “skin on chip” has been delivered. This will open new opportunities for projects with the mentioned industries.
Recently we revealed for the first time the importance of different fibroblast subtypes isolated from the papillary (PFs) or reticular (RFs) layers of the dermis and their generated extracellular matrix (ECM) in invasive behavior of squamous cell carcinoma (SCC) cell lines using 3D-in vitro human skin equivalents. Cell lines representing different stages of SCC in combination with primary keratinocytes were able to invade the ECM produced by RFs while in matrices generated with PFs no invasion was detected. The PFs apparently harbor the capacity to contain cancer cells within the epithelial layer. The invasively growing cancer cells started to express mediators of ‘epithelial-to-mesenchymal’ transition, like TWIST, vimentin and -Catenin. Next, we demonstrated that these protective PFs can differentiate into RFs by TGF-β supplementation, while re-differentiation of RFs into PFs was achieved by targeting the TGF-β receptor using exon-skipping technology or by supplementation of industrial patented compounds. These modulations of the dermal TME enables us to better understand how stromal cells interact with CAFs, TAMs and Th1/2 cells.
Honors and awards
Dr JN Bouwes Bavinck
- 2008: president van SCOPE (Skin Care in Organ Transplant Recipients Europe, www.scopenetwork.org/)
Dr A. El Ghalbzouri
- 2008: ‘Alternatives to Animal Use’ Award for in vitro skin model.
- 2009: Pearl project awarded by Zon Mw to program aiming to develop an in vitro three-dimensional model of primary human cutaneous squamous cell carcinoma
In the upcoming years we will continue our dedicated oncology clinics and aim to extend participation in international collaborations and trials. These efforts are combined with studies aimed at detailed molecular characterization of the subsequent stages of tumor progression, genotype - phenotype correlations and identification of (genetic) risk factors, and individuals at risk that will remain central themes within all three lines of research. In addition, the role of epigenetic factors as well as protein-protein and protein-DNA interactions and functional analysis of candidate genes will be studied using In vitro (3Dskin)models and murine studies. In parallel we will further develop a research line on the interaction of tumor cells with stromal cells and the immune system.
A. Cutaneous lymphoma
The ultimate goal of this research line is to formulate a molecular classification with diagnostic and prognostic markers that will identify patients at risk for a detrimental disease course and develop novel therapeutic approaches that will improve treatment of these patients.
Specific objectives for the following 5 years are:
- We will continue our leadership role in the international biobanking efforts and planned translational studies that are performed within the framework of the international multicentre consortia for cutaneous lymphoma: EORTC Sézary consortium, and the CLIC / PROCLIPI consortium for cutaneous T-cell lymphomas.
- In collaboration with the department of haematology we will further develop participation in clinical trials including EORTC trials, pharma initiated trials and pivotal investigator-initiated proof of principal trials. A specific aim is to combine these trials with systematic biobanking efforts.
- Using material from our cutaneous lymphoma clinic, participation in trials and biobanks from international consortia we will perform molecular studies aimed at identification and validation of prognostic markers and critical survival pathways of tumour cells in collaboration with the department of pathology, haematology, cell biology and clinical oncology (CPT).
- To test therapeutic targets identified by 3 we will invest in further developing functional assays (in vitro and 3D skin explant model from Dr El Ghalbzouri) using small molecule inhibitors and lead compounds.
- In collaboration with Prof S van de Burg and Prof J van Dongen we will develop immunomonitoring tools to investigate the immune response in blood and skin in cutaneous lymphoma patients using state of the art flow cytometry.
- Based on observation from 3-5 we will intensify studies on the interaction of lymphoma cells with the immune system, aimed at development of strategies to activate the immune system against lymphoma cells (immunotherapy).
In the following year we will obtain results from several long-term melanoma genetics projects that will provide leads for subsequent studies and for clinical implementation. Starting this year our research lab shares facilities with the cancer immunology research group led by prof. S van der Burg (department of Clinical Oncology), which creates opportunities for joint studies on the immunology of dysplastic naevi and early-stage melanoma.
Specific objectives for the following 5 years are:
- In the next few years we will have completed analysis of our familial melanoma whole genome sequence analysis data and tested candidate melanoma susceptibility gene variants in the Dutch population. Prime candidate variants will be subjected to detailed functional genetic characterization, including assessment of consequences of the variant on protein function and of the role of the respective genes in melanoma biology in collaboration with dr. AG Jochemsen (Molecular Cell Biology).
- In collaboration with the department of Clinical Genetics we will introduce the testing of new established melanoma susceptibility variants, identified by us and by collaborators of the international consortium, for familial melanoma patients in the clinic. Personalized risk tools based on genotype and phenotype will be introduced improving the clinical management of melanoma families.
- Current genome-wide DNA (hydroxy)methylation analysis and collaborative whole exome sequencing studies on primary melanoma tumour samples will yield genetic and epigenetic events associated with metastatic behaviour. Depending on the functional role and prognostic significance of these (epi)genetic alterations, further molecular and clinical studies will be performed.
- The 3D in vitro melanoma model studies currently performed to assess the contribution of different dermal fibroblast subtypes (papillary and reticular) to melanoma cell invasion may be followed by further analysis of the molecular mediators of pro-invasive heterotypic interactions. Immune cell subsets will be incorporated into the in vitro models enabling tumor immunological studies.
- The clinical utility of Raman spectroscopy as a diagnostic device to distinguish benign from malignant melanocytic tumours will be optimized. The distinct molecular pattern associated with melanoma will be analysed using mass spectrometry methods in collaboration with the Proteomics and Metabolomics group at LUMC (dr. M Giera).
- We will strengthen collaborations with the research the group of prof. S van der Burg and dr. T van Hall (Clinical Oncology) and will expand our melanoma genetics studies to the field of immunology. Pilot studies characterizing the immune infiltrate in (dysplastic) nevus and early-stage melanoma are performed and we aim to develop a joint research line studying the activation of immune responses in cutaneous melanoma and its precursor lesions.
C. Keratinocyte cancers
Specific objectives for the following 5 years are:
- Continued efforts to definitively clarify the role played by human papillomaviruses remain a priority, given the potential implications for new developing powerful new directions for post-transplant SCC treatment and prevention. Human papillomavirus vaccination is one such strategy. Although the cornerstone of anogenital cancer prevention, existing vaccines provide type-restricted protection against alpha rather than betaPV types and so the rationale for their use in cSCC is less convincing. Although the human situation is complicated by uncertainties relating to the highest risk viruses, prevention or timely treatment of specific betaPV infections by vaccination or even antiviral drugs remains a possible future approach for reducing cSCC burden in OTR. We will continue to look for human papillomavirus types that may be important for SCC carcinogenesis.
- We will continue our collaboration with Micronit and Fluigent to develop an “organ (skin)-on-a-chip” system with the aim to better understand the interaction of different cells (e.g. T cells, Macrophages) in a flow system during cancer development. This technology could be a valuable add-on to our existing 3D-disease models and could also contribute to the generation of human (pre-) clinical trials-on-chips and personalized drugs. Within the LUMC, we anticipate to collaborate and contribute to the network of “human organ an disease technology models (hDMT)”.
- We will continue our collaboration with the departments of infectious diseases (Prof. J. van Dissel and Dr. P. Nibbering) and Immune Haematology and Blood transfusion (Dr. JW Drijfhout), in which we have developed an MRSA-burn-wound infection skin model to screen novel anti-microbial peptides (AMPs) developed within the LUMC. In addition, this model will be further used to study the skin microbiome.
- In collaboration with the departments medical oncology and gastroenterology-hepatology we will exploit the unique in-vitro human 3D-cander skin model technology for immunotherapeutic research with our final aim to aid to reveal novel targets and treatment strategies.
Cohesion within LUMC
For cutaneous lymphoma weekly meeting are held with the pathology department to review cutaneous lymphoma biopsies and the haemato-oncology meeting (Prof H Veelken) to coordinate care for patients with advanced disease, while every other week joint clinics are held with radiation oncology (Dr K Neelis and Dr L Daniels). In collaboration with these departments we host a “one-day-staging-track” to optimize clinical care for patients with advanced disease. Trials are performed in collaboration with the department of haematology. At monthly CLEC meetings clinical care and participation within clinical trials is discussed and evaluated.
All patients with melanocytic tumors are seen weekly in a pigmented lesion clinic. Collaborations with radiology and surgery safeguard rapid diagnosis while collaboration with clinical oncology is in place to take care of patients with advanced disease. There is a weekly multidisciplinary melanoma meeting which involves dermatologists, clinical oncologist, surgeons, ophthalmologists, pathologists, radiologists and neurologists. Genetic testing is performed at the ISO certified department of clinical genetics (ISO 15189). Clinical management is coordinated with the society for the detection of hereditary tumors (STOET, Prof. Vasen) that holds a registry for patients diagnosed with familial melanoma. A joint consultation is prepared for patients carrying BAP1-mutations with the department of ophthalmology, radiology and clinical genetics.
Patient care for keratinocyte carcinomas takes place at general clinics and a weekly clinic dedicated to skin care of immunocompromised patients, in particular organ transplant recipients. Epidemiological research on skin cancer in organ transplant recipients , is performed in collaboration with the departments of nephrology and medical microbiology. Every other week patients with complicated tumors are presented at a multidisciplinary meeting with radiation oncology and plastic surgery. One day a week Mohs surgery is performed in collaboration with pathology. Clinical trials on Vemurafenib in basal cell carcinoma and sirolimus in renal transplant recipients were performed in collaboration with clinical oncology.
To optimize collaboration within our group a weekly meeting is in place in which new findings from all three research lines are presented by rotation and critically discussed. In additions principal investigators from all research lines have a monthly meeting with the head of department to coordinate strategy and grant applications and safeguard development of the research line and progress of PhD students. The integration of our research within CPT and supervision of joint PhD students is facilitated by participation of dr PM Jansen (pathology) prof S van de Burg, dr Th van Hall (clinical oncology) and prof Veelken and dr J Vermaat (hematology) at these meetings.
Research on immunomonitoring and tumor characterization by flow cytometry is performed in collaboration with prof JJM van Dongen (Immune haematology) while research on tumour-stromal interactions is performed in collaboration with the CPT labs (clinical oncology, dermatology, ophthalmology and gastroenterology). Combined these collaborations lead to an integrated research line on the interaction of tumour cells with stroma and the immune system.
Clinicopathologic studies are performed with dr PM Jansen (pathology), and studies on genetic and epigenetic changes in tumor cells are performed in collaboration with Prof SM vd Marel (human genetics), prof JJ Goeman, dr SM Kielbasa and dr BT Heijmans (medical statistics) including high-throughput methods for genomic research (like sequencing pipelines and analysis tools) at the Leiden Genome Technology Center and Sequencing Analysis Support Core. Finally studies on the role of human papillomavirus in keratinocyte cancers are performed in collaboration with dr M Feltkamp (medical microbiology).