Doctoral Defence in Health and Medical Sciences – Evangeline Breeta Raja David Isac

On Monday, 24 August, Evangeline Breeta Raja David Isac will defend her doctoral thesis in Health and Medical Sciences at the Faculty of Medicine, University of Iceland. The thesis is entitled: The role of MITF in regulating phenotype switching in melanoma.

The opponents are Dr Geert Berx, Professor at Ghent University in Belgium, and Dr Bylgja Hilmarsdóttir, Assistant Professor at the Faculty of Medicine, University of Iceland.

The principal supervisor and mentor was Eiríkur Steingrímsson, Professor. In addition, the doctoral committee consisted of Erna Magnúsdóttir, Professor; Hans Tómas Björnsson, Professor; Margrét Helga Ögmundsdóttir, Professor; and Robert A. Cornell, Professor.

Sædís Sævarsdóttir, Professor and Dean of the Faculty of Medicine, will chair the ceremony, which will take place in the Ceremonial Hall of the University of Iceland (Hátíðasalur) and begin at 9:00 a.m.

Abstract

Melanoma phenotype switching is a form of cellular plasticity where cells transition between a proliferative, differentiated state and an invasive, mesenchymal-like state. This process is regulated by the Microphthalmia-associated transcription factor (MITF), which acts as a transcriptional rheostat to maintain differentiation and invasion.

This study investigates the molecular mechanisms by which MITF regulates the expression of key epithelial, mesenchymal, and melanocytic genes. The results establish that MITF acts as a direct transcriptional activator of the epithelial marker CDH1 through a specific intronic enhancer. Importantly, MITF activates CDH1 through this intronic element independently of canonical EMT repressors such as ZEB1, SNAI1, and TWIST1. In contrast, while MITF loss leads to gain of the mesenchymal marker CDH2 and invasive phenotype marker SERPINA3, this study suggests that this regulation is mediated through indirect mechanisms. Further mapping of the MITF regulatory network revealed that MITF also binds to intronic enhancers to directly activate the melanocyte marker MLANA and the differentiation promoting factor ZEB2, while its repression of pro-invasive EMT transcription factors remains largely indirect.

To identify novel regulators of this network, a genome-wide CRISPR knockout (GeCKO) screen was performed using newly developed reporter cell lines. The screen identified a pool of upstream repressors wthat actively silence the CDH1 enhancer in both MITF-high and MITF-low conditions. Collectively, these findings establish MITF as a central rheostat that maintains the differentiated state through direct intronic activation of epithelial markers while indirectly suppressing the invasive program, providing a foundation for identifying new therapeutic targets to prevent metastatic progression.

About the Doctoral Candidate

Evangeline Breeta Raja David Isac was born in 1996 in Coimbatore, India. She completed a Bachelor of Technology degree at the Karunya Institute of Technology and Sciences in India in 2018 and a master's degree in Medical and Biomedical Sciences at the University of Sheffield in the United Kingdom in 2020. She began her doctoral studies at the Faculty of Medicine, University of Iceland, in 2021.

Evangeline's parents are Raja David Isac, a retired metalworker, and Jeyakumari Isac, a homemaker. Evangeline's husband is Dr Merlin John Paul, a physician.