Convergent Approaches to Delineate the Metabolic Regulation of Tumor Invasion by Hyaluronic Acid Biosynthesis

Abstract

Metastasis is the leading cause of breast cancer‐related deaths and is often driven by invasion and cancer‐stem like cells (CSCs). Both the CSC phenotype and invasion are associated with increased hyaluronic acid (HA) production. How these independent observations are connected, and which role metabolism plays in this process, remains unclear due to the lack of convergent approaches integrating engineered model systems, computational tools, and cancer biology. Using microfluidic invasion models, metabolomics, computational flux balance analysis, and bioinformatic analysis of patient data, the functional links between the stem‐like, invasive, and metabolic phenotype of breast cancer cells as a function of HA biosynthesis are investigated. These results suggest that CSCs are more invasive than non‐CSCs and that broad metabolic changes caused by overproduction of HA play a role in this process. Accordingly, overexpression of hyaluronic acid synthases (HAS) 2 or 3 induces a metabolic phenotype that promotes cancer cell stemness and invasion in vitro and upregulates a transcriptomic signature predictive of increased invasion and worse patient survival. This study suggests that HA overproduction leads to metabolic adaptations to satisfy the energy demands for 3D invasion of breast CSCs highlighting the importance of engineered model systems and multidisciplinary approaches in cancer research.

Endothelial cells metabolically regulate breast cancer invasion toward a microvessel

“…Using this approach, we demonstrated previously that overproduction of hyaluronic acid (HA) by cancer stem-like cells increases their invasion into a 3D collagen matrix due to elevated glycolytic metabolism. 38 As EC-secreted factors also increased tumor cell invasion and glycolytic metabolism, we speculated that changes in tumor cell stemness may underlie these observations. Interestingly, exposure of MDA-MB-231 reporter cells that express green fluorescent protein (GFP) under control of the stem cell transcription factor NANOG (GFP-NANOG) to HUVEC-CM increased the fraction of GFP high , stem-like cells relative to treatment with CTRL-CM [Figs.…”

Targeting glioblastoma tumor hyaluronan to enhance therapeutic interventions that regulate metabolic cell properties

“…Due to the ubiquity of HA in the brain tissue and tumor microenvironment, several research groups have reported in recent years the role of hyaluronan as a nutrient in tumor progression (7,9,39). Moreover, research has revealed that mitochondrial DNA content is related to survival and that tumor cells activate compensatory pathways to maintain the mitochondrial metabolism (40,41), uncovering the possibility of promising combinatorial treatments.…”

“…Due to the ubiquity of HA in the brain tissue and tumor microenvironment, several research groups have reported in recent years the role of hyaluronan as a nutrient in tumor progression (7,9,39).…”

“…Due to the widely distributed presence in biological tissues and the large array of biological signals, HA has been increasingly used in the design of biomaterial platforms as disease models (5,6). In many tumors, the dysfunctional biosynthesis and signaling of HA involves more threatening cancer progression and therapeutic resistance (7)(8)(9). The control of hyaluronan biosynthesis and degradation may become essential in analyzing the role of HA in tumor biology and predicting the functionality of the multiple molecular weight fragments (10).…”

Phosphoproteomic Changes Induced by Cell-Derived Matrix and Their Effect on Tumor Cell Migration and Cytoskeleton Remodeling

“…Interestingly, culture on CDMs also increased surface-associated HA on tumor cells relative to TCP, a characteristic that has been shown previously to contribute to stemness and invasion (Figure S3B). 57 To further assess whether culture on CDMs stimulates a stem-like phenotype in tumor cells, we performed a limited dilution assay in which MDA-MB-231 cells were first precultured on either TCP or CDMs and subsequently maintained in serum-free, nonadherent conditions. While cells precultured on CDMs and seeded at high densities formed more spheres than cells precultured on TCP, these changes did not translate to an increase in self-renewal as determined using the extreme limited dilution analysis (ELDA) 58 (Figure S3C,D).…”