Understanding how molecular alterations in uveal melanoma lead to tumor dormancy and metastasis

We were the first to identify BAP1 as a gene that is mutated in the majority of uveal melanomas that metastasize and later identified SF3B1 as a gene mutated in cancers less likely to metastasize. PRAME is a transcript which is upregulated in metastasizing tumors, and whose expression is correlated with the presence of SF3B1 mutations. We are investigating novel and state of the art diagnostic processes including molecular analyses of liquid biopsies for the diagnosis of uveal melanoma. We are also investigating how these alterations lead to tumor dormancy by using a 3D cell based model. It is also possible to differentiate eye structures from stem cells and we are engineering these alterations in eye organoids to examine their effects in the differentiation of neural crest of the eye. We will then screen for molecules that disrupt this altered differentiation.

Understanding the cause of chromosomal changes in cancer

Changes in chromosome number were one of the earliest observations in cancer. They can point to the locale of tumor suppressor genes, activated oncogenes or clusters of genes whose expression is altered in tumorigenesis. Understanding the cause of chromosome loss in cancer is critical to understanding tumorigenesis. If this were understood it might also be possible to exploit this knowledge to develop novel treatments for a variety of cancers with chromosome loss (e.g. by treating them as synthetic lethal events).  We are using state of the art DNA sequencing and bioinformatics approaches to understand the cause and consequence of chromosome loss. This includes loss of the entire copy of chromosome 3 in uveal melanoma which is usually associated with loss of function mutations in BAP1.

Understand the consequences of uveal melanoma mutations

We are modeling mutations leading to uveal melanoma in a variety of systems including cell lines, 3D cultures, and eye organoid models to investigate consequences of mutations leading to uveal melanoma and its metastasis. We are also modeling these mutations in the eye and wing of the fruit fly. This will enable us to examine the consequences of genetic mutations in vivo. We will use the results of these findings to develop assays to screen for novel drugs that may combat the effects of cancer causing mutations.

Understanding the genetic basis of acral melanoma

Acral melanoma is a rare melanoma subtype, although its proportion amongst all melanoma is higher in people of color. It is associated with a worse prognosis than cutaneous melanoma overall. We are investigating the genetic basis of acral melanomas in Korean and South African patients. To do this we are performing exome sequencing, a search for gene fusions and copy number analysis. Once plausible genes and mutations are identified we will perform state of the art functional studies to examine the consequences of mutations and search for novel therapeutic interventions.

Identifying and understanding how genetic changes lead to psoriasis and psoriatic arthritis

Psoriasis affects 1-3% of the European population and approximately 30% of patients develop the inflammatory joint disease psoriatic arthritis. One thesis develops there is no cure. We identified CARD14 as a gene mutated in these diseases and determined that disease causing mutations lead to enhanced NF-kB signaling. We are using state of the art genetic and genomic approaches to identify additional genes mutated in psoriasis and psoriatic arthritis, followed by functional studies to examine their effect on immune cell activation and epidermal differentiation.  This includes a study of the effects of altered expression of noncoding RNAs including microRNAs and circular RNAs.