Colorectal cancer (CRC) represents a significant health challenge, with incidence increasing by 5.5 % and mortality by 6.1 % from 2018 to 2020. Improving our understanding of the molecular and biological drivers contributing to CRC progression and response to treatment will help generate new diagnostic tools and apply better personalised therapies. Altered metabolism is a well-recognised but highly heterogeneous characteristic of cancers. It is known to be influenced by both oncogenic drivers and the components of the tumour microenvironment (TME) and is likely to contribute to progression and therapy response. One area of metabolic adaptation in cancer that has revived growing attention in recent years is lipid metabolism. Here we aim to investigate the role of the TME on lipid alterations in CRC pre-clinical models and clinical CRC biopsies using a combination of untargeted ambient mass spectrometry imaging (MSI) in a multimodal fashion with a variety of ex vivo techniques. Desorption electrospray ionisation (DESI) MSI, a type of ambient MSI technique, facilitated the investigation of lipidomic changes within biological tissue with little to no sample preparation. With DESI-MSI, hundreds of biomolecular species can be simultaneously detected while retaining their spatial information without the need for labelling reagents, making it an attractive tool for medical settings. Using HCT-116 xenografts that are characterised by an upregulated phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3-K) activity, a common driver in CRC, lipidomic changes were found in association with increased abundance of phosphatidylinositol lipids possibly linked to the PI3-K pathway and multiple fatty acids (FA) and acylcarnitine species, suggesting altered energy metabolism to fatty acid oxidation (FAO) via the Î²-oxidation pathway. Shifts in oxidative metabolism were also obtained via the analysis of oxygen consumption rate using the Seahorse analyser. This alteration was also apparent in clinical CRC biopsies, were the analysis of primary CRC at different clinical stages as well as primary CRC versus colorectal cancer peritoneal metastasis (CRPM), revealed commonalities in FA species linked to the de novo FA synthesis and dietary FA uptake but differences in FA consumption. Changes in metabolism have also been associated with increased immune cell expression in CRPM compared to the primary CRC biopsies, as determined by the gene expression analysis technique NanoString nCounter. Overall, our data demonstrated that DESI-MSI can be used as a powerful tool to investigate lipidomic alteration in CRC pre-clinical models and clinical biopsies, revealing metabolic changes and key molecular pathways implicated in CRC progression and response to therapy.
|Date of Award
|1 Aug 2023
- The University of Manchester
|Kaye Williams (Supervisor), Adam McMahon (Supervisor) & Omer Aziz (Supervisor)