PXD018300

PXD018300 is an original dataset announced via ProteomeXchange.

Title	Metabolic dependencies in MYCN-driven neuroblastoma
Description	Here we sought metabolic alterations specifically associated with amplified MYCN as nodes to indirectly target the MYCN oncogene. Liquid chromatography-mass spectrometry-based proteomics identified 7 proteins consistently correlated with MYCN in proteomes from 49 neuroblastoma biopsies and 13 cell lines. Among these were phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in de novo serine synthesis. MYCN associated with two regions in the PHGDH promoter, supporting transcriptional PHGDH regulation by MYCN. Pulsed stable isotope-resolved metabolomics utilizing 13C-glucose labeling demonstrated higher de novo serine synthesis in MYCN-amplified cells compared to cells with diploid MYCN. An independence of MYCN-amplified cells from exogenous serine and glycine was demonstrated by serine and glycine starvation, which attenuated nucleotide pools and proliferation only in cells with diploid MYCN but did not diminish these endpoints in MYCN-amplified cells. Proliferation was attenuated in MYCN-amplified cells by CRISPR/Cas9-mediated PHGDH knockout or treatment with PHGDH small molecule inhibitors without affecting cell viability. PHGDH inhibitors administered as single-agent therapy to NMRI-Foxn1nu/nu mice harboring patient-derived MYCN-amplified neuroblastoma xenografts slowed tumor growth. However, combining a PHGDH inhibitor with the standard-of-care chemotherapy drug, cisplatin, revealed antagonism of chemotherapy efficacy in vivo. Emergence of chemotherapy resistance was confirmed in the genetic PHGDH knockout model in vitro. Altogether, PHDGH knockout and inhibition by small molecules consistently slows proliferation, but stops short of killing the cells, which then establish resistance to classical chemotherapy. Although PHGDH inhibition with small molecules has produced encouraging results in other preclinical cancer models, this approach must be considered with caution in patients with neuroblastoma.
HostingRepository	PRIDE
AnnounceDate	2020-12-11
AnnouncementXML	Submission_2020-12-11_02:15:43.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Birte Arlt
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2020-03-31 02:21:41	ID requested
⏵ 1	2020-12-11 02:15:43	announced

Arlt B, Zasada C, Baum K, Wuenschel J, Mastrobuoni G, Lodrini M, Astrahantseff K, Winkler A, Schulte JH, Finkler S, Forbes M, Hundsdoerfer P, Guergen D, Hoffmann J, Wolf J, Eggert A, Kempa S, Deubzer HE, Inhibiting phosphoglycerate dehydrogenase counteracts chemotherapeutic efficacy against MYCN-amplified neuroblastoma. Int J Cancer, 148(5):1219-1232(2021) [pubmed]

submitter keyword: cancer cell metabolism, de novo serine synthesis pathway, one carbon metabolism, cell death, therapy resistance, MYCN

Hedwig E. Deubzer, Stefan Kempa
contact affiliation	Department of Pediatric Hematology and Oncology, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
contact email	hedwig.deubzer@charite.de
lab head
Birte Arlt
contact affiliation	Department of Pediatric Hematology and Oncology, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
contact email	birte.arlt@charite.de
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/12/PXD018300

PRIDE project URI

• PRIDE
  1. PXD018300
     1. Label: PRIDE project
     2. Name: Metabolic dependencies in MYCN-driven neuroblastoma