LOX-catalyzed collagen stabilization is a proximal cause for intrinsic resistance to chemotherapy

Area of Science:

• Oncology
• Cancer Biology
• Tumor Microenvironment

Background:

• The tumor extracellular matrix (ECM) plays a critical role in cancer progression and drug resistance.
• Strategies to modify the ECM for improved therapeutic outcomes are largely unexplored.
• Chemoresistance is often associated with specific alterations in the tumor ECM.

Purpose of the Study:

• To identify targets within the tumor ECM for modification to enhance drug response.
• To investigate the role of collagen and associated enzymes in chemoresistance.
• To evaluate the therapeutic potential of inhibiting collagen stabilization.

Main Methods:

• Analysis of gene expression data from pre-treatment patient cohorts.
• Cross-evaluation of datasets to identify correlations between ECM components and chemoresistance.
• In vitro and in vivo experiments using various tumor models to assess the effects of lysyl oxidase inhibition.
• Assessment of tumor growth, drug response, hypoxia, signaling pathways, and angiogenesis.

Main Results:

• Chemoresistant tumors exhibit increased expression of collagens and collagen-stabilizing enzymes.
• Strong collagen expression and stabilization promote a cycle of hypoxia, malignant signaling, and aberrant angiogenesis.
• Inhibition of lysyl oxidases significantly improved chemotherapy response in diverse tumor models, including metastatic disease.
• Lysyl oxidase inhibition alone could either reduce or enhance tumor growth, depending on the tumor type.

Conclusions:

• Targeting collagen stabilization via lysyl oxidase inhibition is a promising strategy to overcome chemotherapy resistance.
• The tumor's dependence on nutrient supply and tissue stiffness for signaling dictates the effect of ECM modulation.
• Modulating the tumor ECM offers a novel therapeutic avenue for enhancing cancer treatment efficacy.