3D collagen architecture regulates cell adhesion through degradability, thereby controlling metabolic and oxidative stress

Abstract

The collagen-rich tumor microenvironment plays a critical role in directing the migration behavior of cancer cells. 3D collagen architectures with small pores have been shown to confine cells and induce aggressive collective migration, irrespective of matrix stiffness and density. However, it remains unclear how cells sense collagen architecture and transduce this information to initiate collective migration. Here, we tune collagen architecture and analyze its effect on four core cell-ECM interactions: cytoskeletal polymerization, adhesion, contractility, and matrix degradation. From this comprehensive analysis, we deduce that matrix architecture initially modulates cancer cell adhesion strength, and that this results from architecture-induced changes to matrix degradability. That is, architectures with smaller pores are less degradable, and degradability is required for cancer cell adhesion to 3D fibrilar collagen. The biochemical consequences of this 3D low-attachment state are similar to those induced by suspension culture, including metabolic and oxidative stress. One distinction from suspension culture is the induction of collagen catabolism that occurs in 3D low-attachment conditions. Cells also upregulate Snail1 and Notch signaling in response to 3D low-attachment, which suggests a mechanism for the emergence of collective behaviors.

Metabolic Potential of Cancer Cells in Context of the Metastatic Cascade

“…Lung cancer cells are able to bypass such mechanical inhibition through adapting their cytoskeleton and hence maintain high glycolytic rates while other cells in the TME cannot [ 116 ]. In general, the composition of the ECM has an impact on the cell’s metabolic phenotype and also impacts the adhesion and migration efficiency of cells [ 117 , 118 , 119 , 120 , 121 , 122 ].…”

The Thyroid Tumor Microenvironment: Potential Targets for Therapeutic Intervention and Prognostication

“…Stiffness of the extracellular matrix increased glycolysis in both cancer cells and cancer-associated fibroblasts [65]. Similarly, it has been shown that breast cancer cells and fibrosarcoma reduce glucose and glutamine uptake when grown in dense or crowded cellular matrices, and gene set enrichment analysis demonstrated an associated decreased expression of genes involved in the TCA cycle and pyruvate metabolism [66]. Morris and others demonstrated that a metabolic shift occurred in breast cancer cells grown in 3D gels with increasing collagen density, whereby oxygen consumption and glucose utilization by the TCA cycle decreased in high-density collagen gels [67].…”

Recent Advances in Cellular and Molecular Bioengineering for Building and Translation of Biological Systems

“… 112 Further studies suggest that ECM microstructure regulates cell adhesion possibly through mediating matrix degradability, which is necessary for the cells to attach 3D collagen fibrils. 111 In addition, the regulation of Snail 1 and Notch signaling was found, indicating the emergence of collective cell behaviors. The fundamental understanding of the collective behavior of the cells (i.e., VM and alike) may lead to the rational design of biological systems that will fully utilize the power within the cells and ultimately benefit the biological modeling of development and disease.…”