15% of children who die from cancer are victims of neuroblastoma, a paediatric disease that arises from neural cells on the adrenal glands. The MYCN (MYCN amplified) gene, which is the main cause of neuroblastoma and its resistance to treatment, is found in excess copies in nearly half of children with high-risk neuroblastoma.
It has been difficult to treat neuroblastoma by specifically targeting MYCN, according to Dr. Eveline Barbieri, an assistant professor of paediatrics – haematology and oncology at Baylor College of Medicine and Texas Children’s Hospital and the study’s corresponding author. In this work, we looked for metabolic vulnerabilities that we could exploit to break the resistance of these tumours to therapy. The goal was to enhance the survival of children with MYCN amplified neuroblastoma.
Barbieri and her coworkers compared the metabolic profiles of MYCN-amplified neuroblastomas to the profiles of non-MYCN-amplified neuroblastomas using an objective, metabolomics study. Their novel methodology yielded significant differences between the two tumour groups in the way tumour cells utilised particular nutrients to fuel tumour growth.
We discovered that MYCN amplification alters the lipid metabolism of a tumour in a way that encourages the utilisation and manufacture of fatty acids, a kind of lipid that cells can use as a source of energy. Fatty acids play a critical role in the survival of cells with additional copies of MYCN. Both MYCN-amplified cell lines and MYCN-amplified patient tumour samples allowed us to confirm this.
Barbieri and her coworkers compared the metabolic profiles of MYCN-amplified neuroblastomas to the profiles of non-MYCN-amplified neuroblastomas using an objective, metabolomics study. Their novel methodology yielded significant differences between the two tumour groups in the way tumour cells utilised particular nutrients to fuel tumour growth.
“We discovered that MYCN amplification alters the lipid metabolism of a tumour in a way that encourages the utilisation and manufacture of fatty acids, a class of lipid that cells can use as a source of energy. Fatty acids play a critical role in the survival of cells with additional copies of MYCN. Both MYCN-amplified cell lines and MYCN-amplified patient tumour samples allowed us to validate this.” Dr. Eveline Barbieri, a researcher at Baylor College of Medicine, said
Barbieri and her associates proposed that MYCN reroutes lipid metabolism to make fatty acids easily accessible to cancer cells, encouraging the proliferation of tumour cells.
investigating the mechanism
We found that MYCN directly upregulates or improves the production of fatty acid transport protein 2 (FATP2), a molecule that facilitates cellular uptake of fatty acids, when we looked into what caused MYCN-amplified neuroblastomas to depend on fatty acids for growth, said Barbieri. Then, we wondered what would happen if we prevented MYCN-amplified neuroblastomas from functioning properly with FATP2.
The development of MYCN-amplified tumours was inhibited when the researchers neutralised FATP2 activity, either by knocking down the gene or by obstructing FATP2 action with a small molecule inhibitor.
“We found that there was a reduction in tumour cell development when we prevented the import of fatty acids into the cancer cells,” Barbieri added. “It’s interesting to note that normal cells and tumours lacking MYCN-amplification were unaffected by decreasing or blocking FATP2. MYCN-amplified tumours appear to be particularly vulnerable to this metabolic weakness. They have a special transporter that they use to consume fatty acids and develop.”
There are more paediatric and adult cancers amplified for MYCN.
Approximately 50% of all malignancies need MYC for oncogenesis, therefore this method may be applicable to many human cancers and shed fresh light on how energy metabolism is regulated as cancer progresses, according to Barbieri.
These findings imply that therapeutic approaches that disrupt FATP2 activity may preferentially prevent fatty acid uptake in MYCN-amplified tumours, halting or slowing tumour growth and increasing sensitivity to conventional chemotherapy.
Before using this strategy in a therapeutic context, further work must be done, according to Barbieri. “However, our data implies that approaches to disrupt a tumor’s need on fatty acids for sustenance is a viable therapeutic method deserving of additional consideration.”
Source:
Baylor College of Medicine
Journal reference:
Tao, L., et al. (2022) MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma. Nature Communications. doi.org/10.1038/s41467-022-31331-2.