Catherine Van Raamsdonk

Faculty of Medicine

Research Classification

Genetic medicine

Health counselling

Research Interests

cancer genetics

Developmental Genetics

Human Cancer Genetics

Melanocytes

Melanoma

Molecular Genetics

Mouse Genetics and Transgenesis

Oncogenesis

Pigmentation

Relevant Thesis-Based Degree Programs

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Affiliations to Research Centres, Institutes & Clusters

Life Sciences Institute

Research Options

I am interested in and conduct interdisciplinary research.

Research Methodology

Recruitment

Looking to recruit:

Master's students, Doctoral students

Potential research project areas:

Cancer cell metastasis. Neural crest cell development. Molecular analysis of melanocytes and melanoma cells from mouse models: transcriptomics, bioinformatics, proteomics. Primary cell culture, FACS, Immunohistochemistry/Immunofluorescence. Therapeutics and signaling pathways in melanoma.

Other options:

I support experiential learning experiences, such as internships and work placements, for my graduate students and Postdocs., I am interested in supervising students to conduct interdisciplinary research.

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Graduate Student Supervision

Doctoral Student Supervision

Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.

Oncogenic GNAQ and BRAF in epidermal versus non-epidermal melanocytes (2019)

Melanocytic neoplasms represents a group of biologically distinct subtypes that display a wide phenotypic variation. An integrative taxonomy of melanocytic neoplasms have grouped them into two major clades: those that arise from epithelium-associated melanocytes and those that arise from non-epithelium-associated melanocytes. In sites with an epithelial component, e.g. the skin epidermis or conjunctiva of the eye, activating BRAF mutations are frequently found. In contrast, activating GNAQ/11 mutations are virtually absent in those lesions, and instead are frequently found in lesions located in non-epithelial sites, such as the skin dermis, uveal tract of the eye, or meninges, where melanocytes interact with mesenchymal cells instead of epithelial cells. Why does this pattern occur? This question has been the overarching focus of this thesis, with experiments addressing how melanocytes respond to BRAF^V600E and GNAQ^Q209L oncogenes in epithelial and non-epithelial associated melanocytes.It has been suggested that the melanocytic lineage might comprise different subtypes of melanocytes that respond to activation of distinct pathways. Whether this differential response is due to unappreciated differences in the developmental migration of epithelial versus non-epithelial melanocytes, or to different microenvironmental cues sent to mature melanocytes located in different sites has been undetermined. In this dissertation, we found evidence that both developmental processes and microenvironmental cues influence the ability of oncogenes to drive melanocyte transformation. In chapter 2, we characterized a new mouse model for BRAF^V600E driven melanoma targeting melanocytes residing in both epithelial and non-epithelial tissues. Interestingly, non-epithelial melanocytes in the eye or leptomeninges did not respond to oncogenic Braf^V600E signaling. In chapter 3, we found that the timing of GNAQ^Q209L mutation during development influences the subtype of melanoma produced. In chapter 4, we found that the response of mature melanocytes to different oncogenic stimuli is flexible and depends upon environmental signals. Epidermal melanocytes survive poorly in the face of GNAQ^Q209L signaling because paracrine signals from keratinocytes coupled with GNAQ^Q209L signaling make melanocytes more sensitive to cellular stress. They are then lost through apoptosis. However, interactions with fibroblasts have the opposite effect, increasing the ability of GNAQ^Q209L to promote melanocyte transformation.

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The Role of Adamts9 in Melanoblast Migration and Modification of the Skin Proteome (2015)

The glabrous skin, which includes, the tail, the footpads, the nose and the ears, of the mouse retain melanocytes in the dermis, the hair follicles of the epidermis and the interfollicular regions of the epidermis. Given that melanocytes in humans are exclusively found in the epidermis and hair follicles, the epidermis of the glabrous skin of the mouse can be a functional model in the study of melanocytes. A dominant N-ethyl-N-nitrosourea (ENU) mutagenesis screen of C3HeB/FeJ mice at the National Research Center for Environment and Health (GSF) in Germany recovered two mutants, Und3 and Und4. These mice are characterized by a reduction in pigmentation that is localized to the middle regions of the tail, with the base and tip retaining pigmentation. Mapping and sequencing revealed single base pair changes in Adamts9. The mutations in Adamts9 create null alleles and Adamts9, expressed in the epidermis, is required for melanoblast migration in the tail at 18.5 dpc. A conditional knockout of Adamts9 suggests that the hypopigmentation is due to the loss of Adamts9 in melanocytes, but not keratinocytes. Terminal amine isotopic labeling of substrates (TAILS) was used to identify changes in potential cleavage processes between Adamts9Und4/+ and wildtype mice. Several candidates, associated with the stratum basale, were found to be significantly different between the wildtype and the mutant proteomes. These candidates are involved in the regulation of cytoplasmic cell structure (Filamin-A, Filamin-B, beta-tubulin 4A and alpha-tubulin 1C), maintaining the structural organization of cells within the extracellular matrix (Plectin, Desmoplakin, Perisotin and Vimentin) and communication between cells (Type XII collagen, Type VII collagen, Fibrillin-1, Fibronectin, Tenascin and Biglycan). These findings suggest that Adamts9 is essential for the appropriate migration of melanoblasts in the developing embryo and immediately after birth. Additionally, this protease is likely involved in mouse pigmentation by maintaining an environment in the stratum basale that supports the migration of melanoblasts in the epidermis through the activation of proliferation pathways during development. Supplementary video material is available at: http://hdl.handle.net/2429/52938

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Role of Nf1 signaling in regulating pigmentation in the mouse (2012)

Neurofibromatosis type 1 is caused by mutations in neurofibromin (NF1). Neurofibromas, which are Schwann cell based tumors, and skin hyper-pigmentation are characteristic of NF1 loss. Melanocytes differentiate from Schwann cell precursors (SCPs) during development, suggesting that there may be a mechanistic link between these NF1-related manifestations. In this thesis, we use Cre-LoxP technology to test the cell types that require Nf1 for normal pigmentation. We discovered that an Nf1 targeted knockout (Nf1tm1Par) and an ENU-generated N1453K substitution in Nf1 (Nf1Dsk9) are associated with darker skin in mice. Nf1Dsk9/Nf1Dsk9 embryos exhibit increased numbers of melanoblasts at E10.5, and Nf1 -/- knock out in already committed melanoblasts causes dermal and epidermal hyper-pigmentation. In contrast, Nf1Dsk9/+ embryos exhibit an increase in the number of melanoblasts beginning at E12.5, and Nf1 +/- knockout in already committed melanoblasts has no effect on skin pigmentation. Nf1 haploinsufficiency in SCPs causes hyper-pigmentation of the dermis (but not the epidermis) in tamoxifen-inducible Plp1-CreER/+; Nf1tm1Par/+ mice when tamoxifen is administered at E11.5. Consistent with a lack of epidermal darkening in these mice, we found that cells expressing Plp1-CreER at E11.5 do not persist in the adult epidermis.We found that Nf1 regulates skin pigmentation by an endothelin-dependent, as well as an independent mechanism. Nf1Dsk9/+;Ednrbs-l/Ednrbs-l mice lack tail skin pigmentation, like +/+;Ednrbs-l/Ednrbs-l mice. However, Nf1Dsk9/+;Ednrbs-l/Ednrbs-l mice exhibit an increased percentage of pigmented coat compared to +/+;Ednrbs-l/Ednrbs-l mice. Our data suggests that there are at least two mechanisms by which Nf1 regulates pigmentation in mice. Two copies of Nf1 are required to determine the appropriate number of melanoblasts that differentiate from bipotent melanoctye-SCPs. Subsequently, at least one copy of Nf1 is required to restrain the number of melanoblasts in the epidermis and dermis after they have committed to the melanocyte fate. These findings suggest that neurofibromin plays an important role in the specification of melanocytes within the glial lineage and may help design therapeutic options for treating NF1-related hyper-pigmentation in the future.

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Master's Student Supervision

Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.

Molecular mechanisms of BAP1 mutations in uveal melanoma (2021)

Uveal melanoma (UM), a cancer that arises in the eye, is distinguished by activating mutations in either GNAQ or GNA11. These mutations are early events in tumor progression and are often followed by loss of function mutations in BAP1. BAP1 is a deubiquitinase protein that regulates the cell cycle, DNA damage response and cellular differentiation. BAP1 mutations are associated with liver metastasis and worse prognosis in UM. To investigate the effect of BAP1 mutations on a transcriptomic level, we analyzed RNA-sequencing data from primary tumors of UM mouse models and patient data from The Cancer Genome Atlas (TCGA). We performed in-depth differential gene expression analysis, Gene Ontology, Gene Set Enrichment Analysis and KEGG pathway analysis to identify significant pathways and biological processes that are affected as a result of BAP1 loss. In addition, we compared findings from mouse and patient data to validate the enriched pathways and determine their biological significance with relation to the BAP1 function. Using a |Log Fold Change| > 1, our differential expression analysis showed a total of 838 differentially expressed genes in the mouse data and 3118 in the TCGA data in primary tumors with or without BAP1 loss. There were more down-regulated than up-regulated genes in the BAP1 mutant samples from both mouse and patient data. However, the majority of significantly enriched pathways involved up-regulated genes. The enriched pathways and biological processes in both mouse and patient data included neuroactive ligand receptor interaction, leukocyte migration, immune response activation and cytokine production. Comparison of orthologous differentially expressed genes showed significant overlap between the mouse and human datasets. This validates that our mouse model recapitulates the effect of BAP1 loss in primary tumors of UM patients. In addition, the G protein coupled receptor, HTR2B, was consistently up-regulated in human and mouse UM. Up-regulation of HTR2B was previously correlated with a worse prognosis in human UM. To study this candidate gene, we performed HTR2B immunohistochemistry staining of mouse UM with or without Bap1 loss. Further investigation of these pathways is required to shed light on the mechanism in which BAP1 mutations leads to worse prognosis in UM.

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Ocular Melanocytes Respond to Oncogenic GNAQ-Q209L Differently Compared to Epidermal and Dermal Melanocytes in Mice (2015)

Somatic mutations in the homologous human oncogenes GNAQ, and GNA11, are frequently found in ocular melanomas of the uvea, blue nevi of the dermis, and melanocytic neoplasias of the central nervous system (CNS), but rarely in cutaneous melanoma located in the epidermis (0.3%). The most common mutation found in GNAQ/11 is the amino acid substitution Q209L in the Ras-like GTPase domain. It causes complete or partial loss of intrinsic GTPase activity thereby locking the protein in a constitutively active form. To compare the downstream signal transduction effects of GNAQQ²⁰⁹L on melanocytes in different locations such as the dermis, the epidermis, ears, eyes and CNS, the mutant gene was conditionally knocked-in to the ubiquitous Rosa26 locus in mice to normalize gene expression among melanocytes. When expression of GNAQQ²⁰⁹L was induced in melanoblasts (immature melanocytes) during embryogenesis, the mice exhibit hyperpigmentation in the dermis of the tail, footpad, trunk, and ears beginning at a young age, with non-cutaneous melanocyte overgrowth in the inner ear and CNS, and metastatic uveal melanoma in older animals. In older adult mice, a progressive loss of melanocytes occurred in the inter-follicular epidermis, which could explain the lack of GNAQ mutations in human cutaneous melanomas located in the epidermis. When expression of GNAQQ²⁰⁹L was induced in mature melanocytes in adult, some of the above phenotypes such as hyperpigmentation in the dermal skin and uveal track thickening in the eyes were observed. When expression of GNAQQ²⁰⁹L was induced in bipotential Schwann cell precursors, there was a decrease in the number of melanoblasts, suggesting that GNAQQ²⁰⁹L blocks the production of melanoblasts from Schwann cell precursors.Altogether, I developed the first mouse uveal melanoma model driven by oncogenic mutant GNAQQ²⁰⁹L gene. These mice display all three types of lesions driven by constitutively active GNAQ in human: blue nevi, uveal melanoma, and invasive melanocytic neoplasias of the CNS. I show that the downstream effects of GNAQQ²⁰⁹L on melanocytes are strongly dependent upon cellular context, as seen in the differences presented in the epidermis, dermis, uveal and CNS melanocytes.

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