Melanoma discovery and medicine

Programme stream(s): Cancer discovery / underpinning research
Programme session type(s): Specialist session

Chair: Elizabeth Patton, CRUK Edinburgh Centre
Presenter: Sathya Muralidhar, University of Leeds, UK
Speaker: David Adams, Wellcome Trust Sanger Institute, UK
Speaker: Richard Marais, CRUK Manchester Institute, UK
Speaker: Richard White, Memorial Sloan Kettering Cancer Centre, USA

16:35-18:35

Room: Dochart

Melanoma is the most deadly form of skin cancer, and incidence in the UK continues to rapidly rise. While targeted and immune therapies have made important strides toward the treatment of melanoma in the clinic, most people with metastatic melanoma become resistant to therapy and succumb to the disease. This session highlights some of the world leaders in melanoma research who are using unique animal models to develop new drug-bases approaches, explore immune cell biology and visualise metastasising melanoma cells and niches in live animals. This session is designed for basic and clinical scientists interested in using pre-clinical animal models for melanoma biology and drug discovery.

Abstract presentation:
– Transcriptomic data reveal the prognostic and biological significance of the Vitamin D Receptor (VDR) via pro-immune and anti-proliferative mechanisms in a cohort of 703 primary melanomas – Sathya Muralidhar

Adipocytes in the melanoma microenvironment
Speaker: Richard White
Affiliation: Memorial Sloan-Kettering Cancer Center

Abstract:

During metastatic dissemination, tumor cells come into contact with a wide variety of stromal cells in the microenvironment. In melanoma, primary tumors are in direct contact with keratinocytes, but as they progress and then metastasize, they then come into contact with subcutaneous tissues. Although this tissue is largely composed of adipocytes, little is known of the interaction between melanoma cells and adipocytes. Here, we demonstrate that adipocytes in the melanoma microenvironment are a key mediator of melanoma progression. Using a zebrafish model of melanoma, we find that melanoma cells home to adipocyte-rich areas in 57% of cases. Once in contact, the melanoma cells induce lipolysis in the adjacent adipocytes, resulting in the release of fatty acids into the extracellular environment. In turn, the melanoma cells take up these fatty acids through FATP proteins, long chain fatty acid transporters that are aberrantly expressed in ~40% of melanomas. Once inside the melanoma cell, these adipocyte derived lipids cause increases in tumor cell proliferation, invasion and metastasis. Global lipiodomic analysis revealed a core set of fatty acids that are increased in the melanoma cell after exposure to adipocytes. One fate of these lipids is utilization in the β-oxidation pathway to synthesize ATP for energy. However, surprisingly, we found that the acetyl CoA produced via β-oxidation can also be shunted and used for acetylation of histones, leading to global changes in H3K9 and H3K27Ac, along with widespread alterations of transcriptional programs in the melanoma cells. Taken together, our data demonstrate a mechanism by which adipocytes promote tumor progression by providing lipids that can alter the epigenetic state of the nearby cancer cells.

Transcriptomic data reveal the prognostic and biological significance of the Vitamin D Receptor (VDR) via pro-immune and anti-proliferative mechanisms in a cohort of 703 primary melanomas
Speaker: Sathya Muralidhar
Affiliation: University of Leeds

Abstract:

Increased VDR expression within melanoma primaries has been associated with lower stage disease. However, the genomic basis of this effect remains to be understood. 

 

Method

We used clinical (Melanoma Specific Survival -MSS, AJCC stage, tumour site, etc) and transcriptomic data from 703 treatment-naïve primary melanomas (part of the Leeds Melanoma Cohort- LMC) to assess the prognostic significance of VDR expression. VDR-associated candidate pathways/genes were identified by agnostic bioinformatic analyses, which were validated using tumour infiltrating lymphocytes (TILs) and inferred immune cell scores [1]. Finally, in-vitro and in-vivo experiments were used to establish cause and effect.

Results

VDR expression is protective for MSS independent of stage, site, mitotic rate, and TILs (P=0.008). A genome-wide correlation analysis revealed that VDR expression correlated significantly (FDR<5%) and positively with 2025 genes (enriched for immune signalling pathways) and negatively with 1383 genes (enriched for proliferation pathways). 60% of genes known to have a VDR-binding motif are also correlated with VDR expression in our data set. Concordantly, high-VDR tumours had significantly more TILs (P<0.04) and increased immune cell scores (P<10-16) compared to low-VDR tumours. Interestingly high-VDR expression was not associated with variable median VDR copy number or ‘classic’ VDR polymorphisms. An in-vivo metastatic colonisation assay [2] [3] was used to ascribe causal effect to VDR expression by comparing pulmonary metastases area and CD3+ TILs between stable-transfected B16-BL6:VDR mouse melanoma cells and control  B16-BL6 cells (work in progress).   

Conclusion

We used a large cohort of 703 primary melanomas to demonstrate the prognostic significance of VDR expression. Our study is the first to identify the whole-genome correlates of VDR to be associated with pro-immune and anti-proliferative pathways. Taken together, our study aims to provide causal evidence for the pro-immune and anti-proliferative effects of tumour VDR expression.

Precision medicine for melanoma: are we there yet?
Speaker: Richard Marais
Affiliation: CR-UK Manchester Institute

Abstract:

Melanoma is a deadly skin cancer linked to ultraviolet radiation (UVR) and genome sequencing reveals a landscape replete in mutations associated with this environmental insult.   Various subtypes of melanoma are defined by their driver oncogenes; BRAF is mutated in half of common cutaneous melanomas, and NRAS in another 20% of cases.  BRAF and MEK (activated by BRAF) drugs extend patient survival in BRAF mutant melanoma patients, but are less effective in NRAS melanomas signalling re-routes through other pathways to bypass BRAF and MEK inhibition.  Separately, drugs that activate the immune system are effective in 20-60% and can lead to cure independent of the driver oncogene.  The paradigm shift in melanoma care driven by these new drugs has increased patient survival, but most patients still die of their disease.  Acquired and innate resistance limits responses to targeted therapies and it is unclear how patients should be stratified for immunotherapies.  We are using mouse models to examine the relationship between oncogenes and UVR in melanomagenesis and to understand what determines responses to new drugs.  Separately, we are using cell-free tumour DNA (ctDNA) in patient circulation to monitor responses to targeted and immunotherapies to adjust treatment and achieve better patient outcomes.