I’m Alex Websdale, a final year PhD student at the University of Leeds and welcome to my blog post! I’ve been invited to summarise my latest work that was presented at the BACR student conference, winning the executives choice poster award. This work has just been accepted by Oncogene (https://doi.org/10.1038/s41388-021-01720-w)! This paper has been in the works for quite some time, with work beginning around 7 years ago by my supervisor Dr James Thorne. James's first PhD student, my co-first author, Dr Sam Hutchinson (now working at ICR) took on the project for her PhD studies and worked on understanding the molecular mechanism. As Sam was leaving the project transferred to me and I worked on translating the mechanistic understanding to patients. We are all very happy to have had the paper accepted in such a prestigious journal.
To summarise our main finding, the study suggests that greater consideration should be given to the role of cholesterol metabolism inside patients’ tumours, particularly breast cancers that do not express the oestrogen, progesterone and Her2 receptors (triple negative). Cholesterol is the precursor to an array of signalling and functional molecules such as hormones and bile acids. The first step in these metabolic pathways is to add hydroxyl groups to cholesterol creating oxysterols, which are active signalling molecules involved in regulation of cholesterol homeostasis through their agonistic action on the liver x receptor (LXR). Given the link between high cholesterol and associated comorbidities such as obesity, with poor outcomes in some breast cancers treated with chemotherapy, we set out to investigate whether LXR activation could confer chemotherapy resistance. We found that this was indeed the case, and after meeting Dr Erik Nelson a collaboration started to confirm our findings in a mouse breast cancer model. Together we explored the possible mechanisms that may be providing this protection from chemotherapy. We searched for possible candidates by using online cancer data repositories and P-glycoprotein, a membrane pump involved in the export of chemotherapy drugs, became a strong candidate. A series of in vitro experiments proved P-glycoprotein was regulated by LXR in breast cancer cell lines and in the mouse model.
We then wanted to complete our work by testing if the pathway was associated with chemotherapy resistance or survival in actual patients. I visited the laboratory of Dr Hanne Roberg-Larsen (one of my supervisors) in Oslo to learn the liquid chromatography mass spectrophotometry methods required to detect and distinguish between the various oxysterols (they have identical molecular mass and charge, just the position of the -OH group differs). I took frozen TNBC tumours donated by patients to the Leeds Breast Cancer Now Tissue Bank and measured them for each of the different oxysterols. I then paired these samples with measurements of the chemotherapy efflux pumps we had discovered earlier, and found they strongly correlated, and were lower in patients who survived their disease. Immunohistochemical stains against the enzymes responsible for production of the assessed oxysterols similarly found correlations with P-glycoprotein expression and associations with patient survival. This meant the project now had human survival data, a mouse model, and molecular and cell biology showing that these cholesterol metabolites not only associated with worse survival, but that the mechanism was almost certainly via the LXR:P-glycoprotein axis. The group is now working on various aspects of exploiting this discovery in the clinical setting, including recruiting for the PINC clinical trial as soon as COVID-19 restrictions are lifted.
The BACR conference was a fantastic opportunity to present my work. Considering the current situation with COVID-19 online conferences have been really important to enable communication and dissemination of emerging research. I thoroughly enjoyed seeing everyone’s work through posters and presentations. There are certainly some benefits to online conferences (viewing from the comfort of your home in comfortable attire is certainly one!) and I’m sure the decision to split the conference across two days helped some experiments continue across the week, however it’s not quite the same experience without being able to see and present in person. Despite this, the conference was very well organised, and the quality of talks were excellent. Hopefully next year’s conference will be in person!
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