Functional Cancer Proteomics for Precision Medicine in Breast Cancer Metastasis

Abstract

Breast cancer metastasis is relatively poorly understood, particularly with regards to specific organotropism, and remains incurable. Omics analyses of patient-derived breast cancer samples are beginning to elucidate genetic and transcriptomic drivers and predictive biomarkers of breast cancer metastasis but proteomic and phosphoproteomic understanding is limited. The strategy used in this thesis is defined as Functional Cancer Proteomics (FCP) which seeks to use improved sample preparation methods in breast cancer models and patient samples in combination with bioinformatics analysis and functional assays to identify and validate drivers of breast cancer metastasis. I employed the FCP strategy to analyse organotropic variants of the MDA-MB-231 cell line and patient samples with known metastatic status at five years post-diagnosis by mass spectrometry-based proteomics and phosphoproteomics. Endocytosis and protein-trafficking were found to be widely differentially regulated between organotropic MDA-MB-231 variants. Epidermal Growth Factor Receptor (EGFR) trafficking was differentially regulated between parental and lung-tropic MDA-MB-231 cells resulting in an altered interactome and differential downstream EGFR signalling. FCP in breast cancer patient samples identified Osteomodulin (OMD) as a predictor of bone metastasis in breast cancer and as a driver of cell migration, viability and bone colonisation via Cyclin-Dependent Kinase 1 (CDK1) activation. Overall, this work has improved the understanding of mechanisms underlying lung organotropism in cell line models and has identified a potential novel therapeutic pathway in breast cancer bone metastasis. FCP is also a novel strategy for studying metastasis which can be employed in other breast cancer cohorts or other cancers to better understand the mechanisms underlying metastasis and to identify novel predictive biomarkers and therapeutic targets.

Date of Award	17 Feb 2023
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Robert Clarke (Main Supervisor), Ciara O'Brien (Co Supervisor) & Chiara Francavilla (Co Supervisor)