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Goding Group Research Overview

Our interests lie in understanding how phenotypic heterogeneity is generated within cancer, and what are the molecular mechanisms that drive three major barriers to effective therapy: microenvironment-driven metastatic spread, dormancy, and phenotypic drug-resistance. Our long-term aim is to develop effective therapies for cancer that take phenotypic heterogeneity into account.

Using melanoma as a model, we established the key role of the Microphthalmia-associated transcription factor (MITF) in microenvironment-driven phenotype-switching in melanoma biology: MITF-low cells are drug-resistant, slow-cycling, tumour-initiating and invasive, while MITF expression suppresses invasiveness and promotes either proliferation or differentiation. Understanding how MITF is regulated, both transcriptionally and post-translationally, and how it integrates microenvironmental signals to determine melanoma phenotype is a key aim. More broadly, we are interested in how and why invasiveness is imposed and stem cells generated in melanoma, and how similar phenotypic states are produced in non-melanoma cancers.

 

A schematic of the research themes in the Goding lab depicting 4 cellular states: differentiation, proliferation, invasiveness and dormant stem cell. MITF activity is highest in the differentiation state, decreasing in the proliferation and invasiveness states. Drug resistance in relevant in the invasiness and dormant stem cell states. Research questions include: What drives phenotype switching? Why do cells move? How do cells become dormant?

 

Our work has recently introduced the concept of starvation and pseudo-starvation to explain cancer progression. This novel model for cancer progression forms the basis of our work aiming to identify therapeutic vulnerabilities based on the adaptive response of cancer cells to the stresses encountered within the intra-tumour microenvironment.

Our research is therefore aimed at understanding:

  • The drivers of phenotype-switching and senescence
  • The role of starvation and pseudo-starvation in cancer progression
  • The relationship between invasiveness and tumour initiation
  • The molecular mechanisms underpinning dormancy
  • The role of MITF-related factors in non-melanoma cancers
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