TY - JOUR
T1 - MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma
AU - Tao, Ling
AU - Mohammad, Mahmoud A.
AU - Milazzo, Giorgio
AU - Moreno-Smith, Myrthala
AU - Patel, Tajhal D.
AU - Zorman, Barry
AU - Badachhape, Andrew
AU - Hernandez, Blanca E.
AU - Wolf, Amber B.
AU - Zeng, Zihua
AU - Foster, Jennifer H.
AU - Aloisi, Sara
AU - Sumazin, Pavel
AU - Zu, Youli
AU - Hicks, John
AU - Ghaghada, Ketan B.
AU - Putluri, Nagireddy
AU - Perini, Giovanni
AU - Coarfa, Cristian
AU - Barbieri, Eveline
N1 - Funding Information:
We acknowledge Philip Bocock and Scott McCulloch from Metabolon, Inc. for their support with sample preparation and data analysis. We thank Alessandro Baldan for providing primary samples (RTSS, TCH), Brian J. Altman (University of Rochester) for providing SK-N-AS MYCN-ER cells, Ronald Bernardi (BCM, now at Genentech) for providing SK-N-BE(2c) and LAN5 shMYCN cells, Michele Redell (BCM) for providing HS-5 cells, Joel R Neilson (BCM) for providing C2C12 cells, and Huda Zoghbi (BCM) for providing ARPE-19 cells. We thank our master student Nathan Drolet (BCM), summer student Kevin Rodriguez (University of Houston) and visiting post-doc Davide Leardini (University of Bologna) for their technical support. We also thank the Cell-Based Assay Screening Service (BCM), the Stable Isotope Core Laboratory (CNRC, BCM), the Metabolomics Core (BCM) and the Pathology Core (TCH) for their technical support. L.T. is supported by Kate Amato Foundation. E.B. is supported by NIH R01 (R01-CA222224), DOD (W81XWH-19-1-0556), and CPRIT (RP180851). P.S. is partially funded by European Commission, HORIZON 2020 (826121). Y.Z. is partially supported by NIH grant R01CA224304. K.B.G. and A.B. are supported by NIH (NCI/NIDCR 1U01DE028233), St. Baldrick’s Research Grant (714511) and the Russell and Glenda Gordy Center for Innovative Therapies at Texas Children’s Cancer Center. N.P. is supported by NIH/NCI R01CA220297 and NIH/NCI R01CA216426. G.P. is supported by Italian Association for Research on Cancer (AIRC2020-IG24341). T.D.P. and C.C. are partially supported by the NCI P30 shared resource grant (CA125123), CPRIT (RP170005 and RP200504), and NIEHS P30 (ES030285) and P42 (ES0327725) grants. This project is supported by CPRIT Proteomics and Metabolomics Core Facility (RP210227), NIH (P30 CA125123) and Dan L. Duncan Cancer Center. ™
Funding Information:
We acknowledge Philip Bocock and Scott McCulloch from Metabolon, Inc. for their support with sample preparation and data analysis. We thank Alessandro Baldan for providing primary samples (RTSS, TCH), Brian J. Altman (University of Rochester) for providing SK-N-AS MYCN-ER™cells, Ronald Bernardi (BCM, now at Genentech) for providing SK-N-BE(2c) and LAN5 shMYCN cells, Michele Redell (BCM) for providing HS-5 cells, Joel R Neilson (BCM) for providing C2C12 cells, and Huda Zoghbi (BCM) for providing ARPE-19 cells. We thank our master student Nathan Drolet (BCM), summer student Kevin Rodriguez (University of Houston) and visiting post-doc Davide Leardini (University of Bologna) for their technical support. We also thank the Cell-Based Assay Screening Service (BCM), the Stable Isotope Core Laboratory (CNRC, BCM), the Metabolomics Core (BCM) and the Pathology Core (TCH) for their technical support. L.T. is supported by Kate Amato Foundation. E.B. is supported by NIH R01 (R01-CA222224), DOD (W81XWH-19-1-0556), and CPRIT (RP180851). P.S. is partially funded by European Commission, HORIZON 2020 (826121). Y.Z. is partially supported by NIH grant R01CA224304. K.B.G. and A.B. are supported by NIH (NCI/NIDCR 1U01DE028233), St. Baldrick’s Research Grant (714511) and the Russell and Glenda Gordy Center for Innovative Therapies at Texas Children’s Cancer Center. N.P. is supported by NIH/NCI R01CA220297 and NIH/NCI R01CA216426. G.P. is supported by Italian Association for Research on Cancer (AIRC2020-IG24341). T.D.P. and C.C. are partially supported by the NCI P30 shared resource grant (CA125123), CPRIT (RP170005 and RP200504), and NIEHS P30 (ES030285) and P42 (ES0327725) grants. This project is supported by CPRIT Proteomics and Metabolomics Core Facility (RP210227), NIH (P30 CA125123) and Dan L. Duncan Cancer Center.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/6/28
Y1 - 2022/6/28
N2 - Neuroblastoma (NB) is a childhood cancer arising from sympatho-adrenal neural crest cells. MYCN amplification is found in half of high-risk NB patients; however, no available therapies directly target MYCN. Using multi-dimensional metabolic profiling in MYCN expression systems and primary patient tumors, we comprehensively characterized the metabolic landscape driven by MYCN in NB. MYCN amplification leads to glycerolipid accumulation by promoting fatty acid (FA) uptake and biosynthesis. We found that cells expressing amplified MYCN depend highly on FA uptake for survival. Mechanistically, MYCN directly upregulates FA transport protein 2 (FATP2), encoded by SLC27A2. Genetic depletion of SLC27A2 impairs NB survival, and pharmacological SLC27A2 inhibition selectively suppresses tumor growth, prolongs animal survival, and exerts synergistic anti-tumor effects when combined with conventional chemotherapies in multiple preclinical NB models. This study identifies FA uptake as a critical metabolic dependency for MYCN-amplified tumors. Inhibiting FA uptake is an effective approach for improving current treatment regimens.
AB - Neuroblastoma (NB) is a childhood cancer arising from sympatho-adrenal neural crest cells. MYCN amplification is found in half of high-risk NB patients; however, no available therapies directly target MYCN. Using multi-dimensional metabolic profiling in MYCN expression systems and primary patient tumors, we comprehensively characterized the metabolic landscape driven by MYCN in NB. MYCN amplification leads to glycerolipid accumulation by promoting fatty acid (FA) uptake and biosynthesis. We found that cells expressing amplified MYCN depend highly on FA uptake for survival. Mechanistically, MYCN directly upregulates FA transport protein 2 (FATP2), encoded by SLC27A2. Genetic depletion of SLC27A2 impairs NB survival, and pharmacological SLC27A2 inhibition selectively suppresses tumor growth, prolongs animal survival, and exerts synergistic anti-tumor effects when combined with conventional chemotherapies in multiple preclinical NB models. This study identifies FA uptake as a critical metabolic dependency for MYCN-amplified tumors. Inhibiting FA uptake is an effective approach for improving current treatment regimens.
KW - Animals
KW - Cell Line, Tumor
KW - Fatty Acids
KW - N-Myc Proto-Oncogene Protein/genetics
KW - Neuroblastoma/metabolism
UR - http://www.scopus.com/inward/record.url?scp=85132969222&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85132969222&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-31331-2
DO - 10.1038/s41467-022-31331-2
M3 - Article
C2 - 35764645
AN - SCOPUS:85132969222
SN - 2041-1723
VL - 13
SP - 3728
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3728
ER -