Item Details

title

ASSESSING THE EFFECTS OF LYSYL OXIDASE (LOX) AND MATRIX METALLOPROTEINASES (MMPs) INHIBITORS ON THE TUMOR MICROENVIRONMENT USING AN EX-VIVO ORGANOID MODEL

author

Agasthya Reddy, Sai Lasya

abstract

ABSTRACTBackground: Tumor progression and metastasis are influenced by fibrosis in the tumor microenvironment (TME), with collagen dynamics governed by enzymes like Lysyl Oxidase (LOX) and Matrix Metalloproteinases (MMPs). This study takes a unique approach, using tumor organoids incorporating fibroblasts to explore extracellular matrix (ECM) remodeling. We employ LOX and MMP inhibitors β-aminopropionitrile [BAPN], Marimastat, and TGF-β inhibitor (TGF-βi) to understand their effects on the TME. Methods: Liver stellate cells (LX-2) and colorectal cancer cells (HCT-116) were embedded in Type I Collagen to create organoids, treated with BAPN, Marimastat, and TGF-βi. Evaluations at 1 and 6 days included organoid contraction, stiffness (via rheology), and collagen fiber properties (using H&E, Picro Sirius red staining, and image analysis software). Results: Time-dependent ECM remodeling was observed, with initial biomechanical property alterations by tumor spheroids that diminished over time. BAPN impacted collagen mechanics, emphasizing LOX's role in matrix integrity. Marimastat, particularly with TGF-βi, disrupted collagen bundling. The findings indicate ECM changes are mitigated with LOX and MMP inhibition and suggest a potential therapeutic avenue for tumor fibrosis modulation. Conclusion: Targeted enzyme inhibition affects collagen remodeling, suggesting new strategies for managing tumor fibrosis and metastasis. Future work will explore combining these inhibitors with chemotherapeutic drugs.

subject

BAPN

Collagen remodeling

Lysyl Oxidase

Marimastat

Matrix metallo proteinases

Tumor microenvironment

contributor

Soker, Shay (advisor)

Shupe, Thomas (committee member)

Weis, Jared (committee member)

Lee, Sang Jin (committee member)

date

2024-05-23T08:36:24Z (accessioned)

2024-11-22T09:30:10Z (available)

2024 (issued)

degree

Biomedical Engineering (discipline)

embargo

2024-11-22 (terms)

identifier

http://hdl.handle.net/10339/109452 (uri)

language

en (iso)

publisher

Wake Forest University

type

Thesis