Yeesim Khew-Goodall

My research is currently focussed in triple negative breast cancer and neuroblastoma.

Project 1. Triple negative breast cancer (TNBC) (supervised by Prof Khew-Goodall and Dr Ana Lonic) is breast cancer that lacks oestrogen and progesterone receptors and has no HER2 amplification. As such, to date, unlike the other forms of breast cancer, there is a paucity of reliable targeted therapy to treat triple negative breast cancer and chemotherapy remains the standard of care. However, whilst many patients respond well to chemotherapy, about a quarter to a fifth of patients become resistant to chemotherapy and there are few reliable treatment options thereafter. Consequently, there is a need to understand the underlying causes of chemoresistance in triple negative breast cancer.

Our recent studies have identified a signalling pathway – the Fer-PKCδ-PTPN14 axis – that is dysregulated in about 25-30% of triple negative breast cancer patients. Dysregulation of this pathway leads to increased secretion of pro-metastatic factors (Belle et al., 2015), as well as increased oncogenic signalling and better cell survival due to aberrant receptor trafficking (Lonic et al., 2021).

Honours and HDR projects include:

•    Investigating how this pathway affects the response of triple negative breast cancer to current treatments, including its role in influencing both the fate of the cancer cells and the tumour microenvironment.

•    identifying the molecular mechanisms by which this pathway mediates it effects, including identification of kinase substrates and new (previously under-appreciated) roles of post-translational modifications on kinase functions.

•    investigating how dysregulation of the endosomal trafficking mechanisms can lead to cancer progression.

Our laboratory uses phosphoproteomics, functional genomics, spatial transcriptomics, high/super resolution confocal microscopy, genetically modified or xenograft mouse models of triple negative breast cancer and patient breast cancer specimens, as appropriate, for our studies.

Project 2. Neuroblastoma (supervised by Prof Khew-Goodall). Neuroblastoma is a childhood cancer that particularly affects very young children under the age of five, with a median age of diagnosis around one-and-a-half to two years of age. It is a highly heterogeneous cancer of the sympathetic nervous system with some unusual properties that are poorly understood. These include some children with stage 4 cancers that can spontaneously regress without treatment, yet others do not respond to treatment. The lack of reliable targeted therapy for neuroblastoma also means that these children are routinely treated with chemotherapy. However, because of the young age of these patients, even if they recover from the cancer, they can often suffer life-long debilitating outcomes. Our studies are based on the hypothesis that neuroblastoma arise from a failure of complete differentiation of the trunk neural crest cells to sympathetic neurons and it is the intermediate, incompletely differentiated neuroblasts that go on to become cancerous.

Honours and HDR projects:

•    will take the approach of understanding the process of differentiation and maturation of neuroblasts to sympathetic neurons to identify critical signalling pathways of the differentiation and maturation program, using induced pluripotent stem cells (iPSCs).

•    use data on neuroblast differentiation to identify and understand how dysregulated signalling pathways can lead to neuroblastoma in patients.

•    Using CRISPR-edited iPSCs to model the disease to identify potential new therapeutic targets.

These studies will be carried out using state-of-the-art sequencing strategies for coding and non-coding RNAs, bioinformatics and spatial transcriptomics using mouse embryos and patient samples. These studies are part of a large collaborative team which includes those of Associate Professor Quenten Schwarz and Professor Greg Goodall at the Centre for Cancer Biology.