Extracellular Matrix Sulfation in the Tumor Microenvironment Stimulates Cancer Stemness and Invasiveness

Area of Science:

• Biochemistry
• Cancer Biology
• Biomaterials Science

Background:

• Tumor extracellular matrices (ECM) show altered composition and mechanics.
• Proteoglycans (PG) regulate cell signaling in ECM via sulfated glycosaminoglycan (sGAG) chains, but their role in cancer is debated.

Purpose of the Study:

• Investigate the role of PGs in lung adenocarcinoma (LUAD).
• Develop a bioengineered model to study sGAGs' impact on tumor cells.
• Identify molecular mechanisms linking sGAGs to tumor cell behavior.

Main Methods:

• Analysis of PG expression in LUAD patient tumors.
• Development of an organotypic lung tumor model with tunable matrix properties.
• Utilized integrative omics and network modeling for transcriptomic analysis.

Main Results:

• PGs are highly expressed in LUAD, correlating with invasive phenotypes and poor prognosis.
• Increased sGAGs in the bioengineered model stimulated cancer cell proliferation, epithelial-mesenchymal transition (EMT), and stemness.
• The focal adhesion kinase (FAK)-phosphatidylinositol 3-kinase (PI3K) signaling axis, activated by specific receptor tyrosine kinases (RTKs), mediates sulfation-induced changes.

Conclusions:

• Elevated sGAGs in the tumor microenvironment promote LUAD progression.
• The FAK-PI3K pathway is a key mediator of sGAG-driven cancer cell behaviors.
• The bioengineered model effectively recapitulates tumor-specific transcriptomic changes observed in patients.