Elucidating the role of hyaluronic acid in solid tumour associated extracellular matrix

Abstract

Solid tumours are more than just cancer cells; they are intricate ecosystems comprised of various cell types, blood vessels, extracellular matrix (ECM), and signalling molecules. The ECM is a complex network of fibrous proteins, macromolecules and signalling molecules providing biomechanical and biochemical support to surrounding cells. The dysregulation of the ECM contributes to cancer initiation and progression. One component of the ECM whose dysregulation and increased expression in the tumour-ECM results in a more aggressive cancer phenotype is Hyaluronic Acid (HA).

We identified a HA deposition and degradation imbalance across human cancers using in-silico profiling of HA synthases and hyaluronidases (Hyal), HA degrading enzymes, RNA, with increased HA accumulation correlated with reduced patient survival. The specific role of HA within the tumour’s ECM remains ambiguous, making it essential to discern its cancer-promoting role and potential for therapeutic intervention. We hypothesise that local delivery of Hyal to the tumour would remodel the HA-ECM and provide insight into HA's mechanistic and therapeutic role. Building on this, we developed a novel cell-based approach; we generated genetically engineered mesenchymal stromal cells (GEMesys) to express Hyal. Hyal-expressing GEMesys successfully degraded HA, remodelled the collagen matrix, and rewired the immunosuppressive and hypoxic environment in in vivo syngeneic murine models. We established the therapeutic efficacy of our GEMesys, especially their synergistic potential when combined with agents like CDDP/DOX and Cy/Flu. However, achieving long-term curative effects necessitates further refinement in dosage and treatment.

In this thesis, I demonstrate the multifunctional nature of HA in tumours, from acting as a physical barrier and promoting immune evasion to engaging with pro-oncogenic signalling pathways. Importantly, our findings highlight the advantages of degrading HA in the ECM to enhance tumour susceptibility to treatment, emphasising the therapeutic potential of our GEMesys. Hyal-expressing GEMesys are a novel approach in the fight against cancer centred on HA remodelling, a treatment strategy we hope to advance into the clinic for patients.

NOT FOR CONSULTATION: Thesis embargoed in perpetuity. 

Date of Award	Jul 2024
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	National Institutes of Health
Supervisor	Emma Kerr (Supervisor), Rosandra Kaplan (Supervisor) & Nick Orr (Supervisor)