Poster #002, UCSF
Lysyl-oxidase -Driven Extracellular Matrix Stiffness Drives Breast
Cancer Metastases
Mentor: Moses Musiime Ph.D Postdoc
Cancer occurs when cells grow uncontrollably in the tissue, creating a cancerous tumor that can metastasize (spread into other parts of the body). Breast cancer tissue is characterized by excessive deposition and crosslinking of extracellular matrix (ECM), mainly collagen, leading to increased stiffness and fibrosis. The excessive crosslinking in the cancer cell is due to an upregulation of an enzyme called Lysyl oxidase (LOX) that serves as a catalyst for collagen crosslinking in the ECM. Increased stiffness due to upregulation of LOX, which leads to fibrosis, has been shown to increase breast tumor progression and poor survival outcomes; however, studies elucidating the role of LOX-driven breast tissue stiffness and fibrosis are still poorly understood. In this study, we aimed to understand how Lox-driven ECM stiffness drives breast cancer metastases to the lungs. To address this gap, we generated an inducible mouse model, Platelet-Derived Growth Factor (PDGFR-beta)-cre Lox f/f FVB line, to ablate LOX in the stromal fibroblast population. First, we confirmed tissue-specific LOX ablation, and then we crossed it with PyMt FVB to create murine mammary-specific tumours with high metastatic potential. Cohorts of the mouse model were monitored for 11 weeks to assess the impact on primary tumours and stromal phenotype. We collected breast tissue and lungs to monitor for tumor volume, phenotype, and lung metastasis. Ablation of stromal-fibroblast LOX significantly reduced tumour volume, fibrosis, including fibrillar collagen, and stiffness. H&E (Hematoxylin and Eosin) staining revealed a reduced number of metastases in the LOX knockout. Immunostaining revealed reduced expression of Epithelial-Mesenchymal Transition (EMT) markers Zeb1 and Slug. These findings demonstrate that stromal LOX regulates metastatic programs and stresses the importance of fibrosis, extracellular matrix, and stromal stiffening in breast cancer progression.