White Group Research Overview

Developmental programmes are central to the way in which tumours attain new phenotypes above and beyond their genetic changes. Such phenotype plasticity is relevant to both tumour initiation as well as metastasis, the major cause of cancer mortality. We have made major discoveries regarding the role of developmental programmes in tumour initiation (oncogenic competence), how anatomic/positional gene programmes determine which genes are transforming (oncogenic specificity) and how tumour cells interact with the microenvironment to promote metastasis. Major areas of interest include:

Developmental neural crest programmes and oncogenic competence

Using a transgenic model of BRAFV600E-induced melanoma, we discovered that tumour initiation requires establishment of a permissive neural crest programme which includes genes such as SOX10, TFAP2, and crestin (White et al. 2011; Kaufman et al. 2016). Using a combination of in vivo imaging, genetics and chemical screens, we initially identified genes involved in transcriptional elongation (i.e. DHODH, SPT5, HEXIM1) as a key regulatory step in the expression of these neural crest genes.

We more recently asked why some developmental stages were more susceptible to BRAF. Using a combination of zebrafish and human pluripotent stem cell models, we found that neural crest and melanoblast cells were much more susceptible to BRAF compared to melanocytes. Further investigation revealed that a large number of chromatin modifying genes (e.g. ATAD2, CHD9, BAZ1A and others) are intrinsically expressed at much higher levels in the neural crest or melanoblasts compared to the melanocytes. One key factor is ATAD2, which we found leads to greater chromatin accessibility at neural crest loci and interacts with both SOX10 and components of the BRAF/MAP kinase pathway. Expression of ATAD2 in melanocytes makes them permissive for oncogenic transformation by BRAF. This establishes a paradigm in which developmental chromatin programmes are a determinant of how those cells respond to DNA mutations, which we refer to as oncogenic competence (Baggiolini et al. 2021).

Using a zebrafish melanoma model and human pluripotent stem cell-derived cancer model to study BRAF-V600E in neural crest cells, melanoblasts or melanocytes. High levels of developmental chromatin factors (e.g. ATAD2) in the neural crest cells and melanoblasts gives high oncogenic competence. Absence of ATAD2 in melanocytes gives low oncogenic competence.

Anatomic gene programmes and oncogenic specificity

While developmental chromatin state is one dimension of oncogenic competence, not all cells respond to the same DNA alteration. While BRAF-driven melanomas typically arise on the trunk, a subtype called acral melanoma arises on the limbs. These melanomas are driven by amplification of genes such as CRKL, rather than BRAF.

Using our zebrafish models, we demonstrated that CRKL-driven melanomas arose on the fins of the fish, the evolutionary precursors to tetrapod limbs. We found that the anatomic localisation of these tumours depends on the transcriptional programme of melanoblasts in those parts of the body, primarily a HOX13 positional identity programme. ChIP-seq revealed that HOX13 specifically promotes an insulin-IGF driven programme in the limbs, and that this signalling pathway synergises with CRKL to drive these anatomically restricted tumours. This indicates that adult cells retain their developmental identity with respect to anatomic position, and that this intrinsic transcriptional identity is what determines what DNA alterations the cell will respond to (Weiss et al. 2022).

HOX13 expression drives the IGF/insulin signalling pathway in the limbs which, in combination with CRKL, drives these anatomically restricted tumours.

Cell-cell interactions with the microenvironment

Advanced melanomas grow into the subcutaneous tissue, encountering an entirely new microenvironment. This environment is dominated by adipocytes, the lipid storage cell beneath the skin. We found that adipocytes act as fatty acid donors, in which the lipids are secreted into the extracellular space and then actively taken up by the melanoma cell by the FATP lipid transporters. The melanomas exposed to the adipocyte-derived lipids adopted an invasive gene signature and endowed the tumours with markedly enhanced metastatic ability. These lipids act as both signalling molecules but are also metabolised via ß-oxidation. This causes widespread changes in histone acetylation and chromatin architecture of the melanoma cell. These observations led to the idea that microenvironmental adipocytes can drive metastasis via changes in both metabolism and the epigenetic state of the cancer cell (Zhang et al. 2018; Huang et al. 2022).

Adipocytes release lipids, which are taken up by the FATP transporter on the surface of melanoma cells to promote an invasive/metastatic cell fate.

Ongoing areas of research

Our goal over the next several years is to more deeply understand how cell-intrinsic developmental programmes are influenced by interactions with the microenvironment. We have a particular interest in understanding the role of anatomic position and positional identity gene programmes. These have a major influence on response to oncogenes, interactions with the local microenvironment, and influence of systemic factors like hormones.