Using melanoma as a model for a highly invasive, heterogeneous and plastic cancer type, we aim to elucidate the molecular mechanisms that drive the adaptive responses that enhance survival of cancer cells in response to changes in the intra-tumour microenvironment. Of particular interest is the generation of the dormant or cancer stem cell state and identification of novel therapeutic vulnerabilities.
Using single-molecule-tracking, inducible ChIP-seq and fluorescence-anisotropy we showed how pro-proliferative signalling can alter the activity of the master regulator of pigment cell and melanoma phenotype, MITF, through post-translational modifications. The findings explain how MITF acts as a lineage survival oncogene as well as MITF amplification during acquired resistance to MAPK inhibitors, the first line of defence for patients harbouring activating BRaf-mutations, a hallmark of melanoma.
To better understand the influence of hypoxia and nutrient limitation, we used genomic approach (RNA-seq and ChIP-seq) on melanoma cell lines representing distinct phenotypic states over a time-course to enable us to profile short and long-term transcriptional responses that drive the adaptive response. These studies revealed surprising cell line-specific transcription reprograming as well as activation kinetics of some commonly regulated genes. We also investigate the synergistic effect of distinct microenvironmental cues on cellular phenotype.
Translating our findings on how MITF integrates microenvironmental signals and cellular bioenergetics to control the adaptive responses implicated in the generation of dormant/stem-like cells in melanoma to other cancer types, we are now exploring the MITF-related MiT transcription factors, which are ubiquitously expressed across many tissues. Therapies that suppress MiT function should have a significant therapeutic benefit in broad cancer types. To this end, we are utilising high-content imaging of cells treated with FDA-approved drugs to identify compounds that can inhibit MiT function with the end-goal of identifying compounds that interfere with cellular adaptive responses to stresses and consequently the eradication of the dormant, conventionally therapy-resistant population.
2015-Present: Oxford Ludwig Institute, Postdoctoral Molecular Biologist/Bioinformatician
2010-2015: University of Oxford, DPhil, Clinical Medicine
2009-2010: Princeton University, Lewis-Sigler Institute for Integrative Genomics, Master Research student
2006-2010: University of Oxford, MBiochem, Molecular and Cellular Biochemistry
The MITF-SOX10 regulated long non-coding RNA DIRC3 is a melanoma tumour suppressor.
Coe EA. et al, (2019), PLoS genetics, 15
Lineage-Restricted Regulation of SCD and Fatty Acid Saturation by MITF Controls Melanoma Phenotypic Plasticity.
Vivas-García Y. et al, (2019), Molecular cell
is activated by MITF andβ‐catenin and is associated with melanoma differentiation
Louphrasitthiphol P. et al, (2019), Pigment Cell & Melanoma Research
MITF controls the TCA cycle to modulate the melanoma hypoxia response.
Louphrasitthiphol P. et al, (2019), Pigment Cell Melanoma Res
BRN2 suppresses apoptosis, reprograms DNA damage repair, and is associated with a high somatic mutation burden in melanoma.
Herbert K. et al, (2019), Genes Dev, 33, 310 - 332