# Collateral Impact of Mannose Supplementation on Metastatic Properties in Osteosarcoma Cell Models

## TL;DR

Mannose supplementation reduces the spread of osteosarcoma cells by affecting their metabolism and key metastasis-related genes.

## Contribution

The study reveals that mannose supplementation inhibits osteosarcoma cell growth and metastasis through MPI-linked metabolism.

## Key findings

- Mannose supplementation dose-dependently inhibits the growth of high-metastatic osteosarcoma cells.
- Mannose reduces migration and invasion abilities of osteosarcoma cells.
- Mannose downregulates key metastasis-related genes in osteosarcoma cell models.

## Abstract

Osteosarcoma is a rare but aggressive bone cancer that mainly affects children and teenagers, and its tendency to spread makes it very difficult to cure. Recently, supplementation with mannose, a natural sugar closely related to glucose, has been shown to slow the growth and spreading of cancer cells by exploiting their altered sugar metabolism, which has been explored as a metabolic perturbation in preclinical cancer models. This study examined osteosarcoma patient transcriptome data and found that GPI was significantly upregulated in tumor tissue compared with paired normal bone, whereas other glycolysis- and mannose-metabolism genes showed modest, non-significant upward trends. Then we investigated the effect of mannose supplementation in osteosarcoma cell lines and found the dose-dependent effect of mannose supplementation on growth retardation, especially in cells with high metastatic potential. Parallel with this finding, mannose supplementation also reduced their ability to migrate and to invade, as a progression marker of osteosarcoma. In addition, we showed that mannose supplementation repressed gene expression of several genes that drive metastasis. Our findings suggest mannose metabolism as a tractable vulnerability in osteosarcoma cell models and motivate future in vivo work to test whether modulating mannose availability can complement existing therapies.

Mannose supplementation has emerged as a promising strategy to exploit the hidden vulnerabilities of cancer cells. However, the mannose-dependent effect on cellular functions remains unclear. Here, we investigated the collateral impact of mannose supplementation on the metastatic potential of osteosarcoma. Analysis of a paired osteosarcoma dataset showed significant upregulation of GPI in tumors compared with matched normal tissue, whereas other glycolysis- and mannose-metabolism genes showed non-significant upward trends. By using osteosarcoma cell lines, MG-63 carrying a pronounced epithelial-to-mesenchymal transition phenotype showed a dose-dependent inhibition of proliferation upon mannose supplementation. We also found that mannose-induced attenuation of cell growth was further enhanced, accompanied by marked reductions in migration and invasion ability. Consistently, qPCR analysis indicated that mannose supplementation downregulated key genes associated with metastasis. Collectively, our data reveal that mannose inhibits osteosarcoma not merely by dampening glycolysis but also by triggering, in part, MPI-linked mannose metabolism, which disrupts key drivers of motility-associated phenotypes. Together, these data show that pharmacologic mannose supplementation modulates cell growth- and motility-associated phenotypes in osteosarcoma cell models, accompanied by changes in epithelial-to-mesenchymal transition-associated transcripts.