Neuroblastoma, a childhood cancer that arises from neural cells on the adrenal glands, is responsible for 15% of childhood cancer deaths. Nearly half of children with high-risk neuroblastoma harbor extra copies of the gene MYCN (MYCN amplified), the major cause of neuroblastoma and its resistance to therapy.
“Treating Neuroblastoma by Targeting Directly” MYCN has been challenging,” said Dr. Eveline Barbieri, corresponding author of a recent study published in the journal nature communication and assistant professor of pediatrics – hematology and oncology at Baylor College of Medicine and Texas Children’s Hospital. “In this study, we explored novel strategies to improve the survival of children with MYCN amplifies neuroblastoma by looking at metabolic vulnerabilities that we could leverage to overturn these tumors’ resistance to therapy.”
Barbieri and her colleagues used an unbiased, metabolomics analysis to analyze the metabolic profiles of MYCN-enhanced neuroblastomas to the profiles of non- MYCN-enhanced neuroblastomas. The results of their innovative approach showed that there were important differences between tumor cell utilization of specific nutrients for tumor growth in these two tumor groups.
“We have found that MYCN amplification rewires a tumor’s lipid metabolism in a way that promotes the utilization and biosynthesis of fatty acids, a type of lipid cells that can be used as an energy source,” Barbieri said. “Cells with extra copies of MYCN are highly dependent on fatty acids for their survival. We have this in both MYCN-amplified cell lines and in MYCN- amplified tumor samples from patients.”
Barbieri and her colleagues hypothesized that: MYCN redirects lipid metabolism so that fatty acids are readily available to cancer cells, promoting tumor cell growth.
Looking into the mechanism
“When we investigated what the trigger was” MYCN-enhanced neuroblastomas to rely on fatty acids to grow, we found MYCN directly upregulates or enhances the production of fatty acid transporter 2 (FATP2), a molecule that mediates the cellular uptake of fatty acids,” Barbieri said. MYCN-enhanced neuroblastomas?”
When the researchers neutralized FATP2 activity, either by knocking down the gene or blocking the action of FATP2 with a small molecule inhibitor, they reduced the growth of MYCN-enhanced tumors.
“We noticed that when we blocked the input of fatty acids into the cancer cells, there was a decrease in tumor cell growth,” Barbieri said. “Interestingly, inhibiting or blocking FATP2 had no effect on normal cells or tumors without MYCN-strengthening. This appears to be a selective metabolic vulnerability of MYCN-enhanced tumors. They uniquely use this transporter to feed on fatty acids to grow.”
There are others MYCN-enhanced pediatric and adult tumors.
“This approach may be applicable to many human cancers that use MYC for oncogenesis (about 50% of cancers overall) and provide new insight into the regulation of energy metabolism in cancer progression,” Barbieri said.
This finding suggests that therapeutic interventions that interfere with FATP2 activity may selectively block fatty acid uptake MYCN-enhanced tumors, stopping or reducing tumor growth and making them more sensitive to conventional chemotherapy.
“More work is needed before this approach can be applied in the clinical setting,” Barbieri said. “But this study suggests that strategies to interfere with a tumor’s dietary dependence on fatty acids are a promising therapeutic strategy worthy of further investigation.”
Other contributors to this work include first author Ling Tao and Mahmoud A. Mohammad, Giorgio Milazzo, Myrthala Moreno-Smith, Tajhal D. Patel, Barry Zorman, Andrew Badachhape, Blanca E. Hernandez, Amber B. Wolf, Zihua Zeng, Jennifer H Foster, Sara Aloisi, Pavel Sumazin, Youli Zu, John Hicks, Ketan B. Ghaghada, Nagireddy Putluri, Giovanni Perini and Cristian Coarfa. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, Dan L Duncan Comprehensive Cancer Center, National Research Center-Cairo, University of Bologna, Texas Children’s Hospital, and Houston Methodist Hospital.
This study was supported by the Kate Amato Foundation and the Department of Defense (W81XWH-19-1-0556). See the publication for a full list of funding for each study author.
Materials supplied by Baylor College of Medicine. Originally written by Molly Chiu. Note: Content is editable for style and length.