E-Poster 63rd Endocrine Society of Australia Annual Scientific Meeting 2020

Proteomic profiling of hormone-dependent prostate cancer identifies LOXL2 as a potential therapeutic target in the tumour microenvironment. (#51)

Natalie L Lister 1 2 , Elizabeth V Nguyen 3 , Brooke A Pereira 4 , Mitchell G Lawrence 1 2 5 , Thomas R Cox 4 6 , Gail P Risbridger 1 2 5 , Renea A Taylor 1 2 5 , Roger J Daly 1 3
  1. Cancer Program, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
  2. Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia
  3. Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
  4. Cancer Division, The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW, Australia
  5. Sir Peter MacCallum , Department of Oncology, The University of Melbourne , Parkville, Melbourne, Australia
  6. Faculty of Medicine, St Vincent’s Clinical School, UNSW Sydney, Sydney , NSW, Australia

Introduction: The prostate tumour microenvironment plays a key role in prostate cancer disease progression. Although current therapies primarily target the tumour epithelium, resolving how tumour cells interact with their surrounding microenvironment may offer novel therapeutic targets. Cancer-associated fibroblasts (CAFs) are found within or near tumour regions and have been shown to promote prostate cancer progression compared to fibroblasts from non-malignant regions of the prostate (NPFs).

Methods: Four pairs of patient-matched CAF and NPF stromal cells were isolated from patients undergoing radical prostatectomy for primary, castrate-sensitive prostate cancer. To identify potential target proteins within the tumour microenvironment, the proteome and phosphoproteome of CAF/NPF populations were characterised by liquid chromatography-tandem mass spectrometry (LC-MS/MS) with a hyper-reaction monitoring data-independent acquisition (HRM-DIA) workflow.

Results: STRING analysis of the CAF proteome revealed a prominent protein interaction hub associated with collagen synthesis, modification, and signaling within the extracellular matrix (ECM). CAFs expressed multiple proteins that regulate a pro-tumourigenic extracellular matrix, including lysyl oxidase-like 2 (LOXL2), which promotes collagen crosslinking and tumour ‘stiffness’. Importantly, our data demonstrates that pharmacological inhibition of LOXL2 in CAF perturbed extracellular matrix (ECM) organization and impaired the motility of prostate tumor cells in a co-culture assay.

Conclusion: CAF-derived LOXL2 is an important mediator of intercellular communication within the prostate tumor microenvironment and a potential therapeutic target. Next generation selective inhibitors of LOXL2 show promise for therapeutic treatment of solid tumours.