ESR06 – Sathya Muraldihar – based in Leeds

Project Title: Establishing the role of smouldering inflammation in suppression of adaptive immunity and therefore survival from melanoma.
PhD awarded: December 2019

I have been fascinated by cancer ever since I realised that it is caused not by foreign germs, but by rogue cells within our own selves. This fascination led me to major in Cancer Biology at the German Cancer Research Centre in Heidelberg, thus helping me understand the disease better. Fascination eventually became an obsession, motivating me to conduct cancer research as part of my PhD. Being part of MELGEN, my research aims to understand how melanoma is influenced by genetic factors as well as our own immune system, thus leading to the possibility of more effective detection and treatment choices for melanoma patients.

When I’m not dabbling with science I enjoy cooking, painting, travelling and practicing yoga. I am also a movie buff and an ardent science fiction fan, which often help me realise that facts and fiction are not very far apart!


Research Summary

My PhD project was to understand the role of vitamin D in melanoma. Previous research suggested that melanoma patients with higher vitamin D levels in their blood were more likely to have less aggressive melanomas and improved survival. However, the mechanism behind this effect was not fully understood. As part of my PhD project, I studied the relationship between patients’ vitamin D levels and their melanomas, by focusing on the genetic material from the melanomas. My research revealed that the effect of vitamin D levels on patient prognosis was strongly linked to the expression of a specific gene: the vitamin D Receptor, also known as VDR. This could be owing to the fact that vitamin D is dependent on VDR in order to be effective. Patients whose tumours expressed high levels of VDR were also likely to have reduced expression of genes that accelerated cancer growth and increased expression of genes involved in immunity. This finding suggested that having high levels of vitamin D and VDR went hand in hand with reduced cancer growth and improved immune response. This could potentially explain why these patients had improved survival over those who had lower levels of vitamin D and VDR. To test if this ‘cause-effect’ relationship was true, I performed laboratory experiments where I artificially increased the production of VDR in melanoma cells grown in the lab. This experiment was meant to mimic the comparison of two sets of patients whose melanomas had either very high or very low VDR expression. The melanoma cells with high VDR production grew slower and were less aggressive compared to cells with low VDR production. This finding was very similar to the effects observed in patients. This led me to conclude that vitamin D levels in the blood and VDR production in melanomas affect the growth of the cancer by forcing it to grow slower and to attract more cancer-killing immune cells. My research could have an impact on how melanoma patients will be treated in the future, taking into account the vitamin D levels in their blood.

Publications

Nsengimana J, Laye J, Filia A, O’Shea S, Muralidhar S, Poźniak J, Droop A, Chan M, Walker C, Parkinson L, Gascoyne J, Mell T, Polso M, Jewell R, Randerson-Moor J, Cook GP, Bishop DT, Newton-Bishop J. β-Catenin-mediated immune evasion pathway frequently operates in primary cutaneous melanomas. J Clin Invest. 2018 May 1;128(5):2048-2063. Available at: https://www.jci.org/articles/view/95351

Poźniak J, Nsengimana J, Laye JP, O’Shea SJ, Diaz JMS, Droop AP, Filia A, Harland M, Davies JR, Mell T, Randerson-Moor JA, Muralidhar S, Hogan SA, Freiberger SN, Levesque MP, Cook GP, Bishop DT, Newton-Bishop J. Genetic and Environmental Determinants of Immune Response to Cutaneous Melanoma. Cancer Res. 2019 May 15;79(10):2684-2696. Available at: https://cancerres.aacrjournals.org/content/79/10/2684

Muralidhar S, Filia A, Nsengimana J, Poźniak J, O’Shea SJ, Diaz JM, Harland M, Randerson-Moor JA, Reichrath J, Laye JP, van der Weyden L, Adams DJ, Bishop DT, Newton-Bishop J. Vitamin D-VDR signaling inhibits Wnt/beta-catenin-mediated melanoma progression and promotes anti-tumor immunity. Cancer Res. 2019 Dec 1;79(23):5986-5998. Available at: https://cancerres.aacrjournals.org/content/79/23/5986.