PXD027175

PXD027175 is an original dataset announced via ProteomeXchange.

Title	Mitochondrial One-Carbon Flux has a Growth-Independent Role in Promoting Breast Cancer Metastasis
Description	Progression of primary cancer to metastatic disease is the most common cause of death in cancer patients with minimal treatment options available. Canonical drugs mainly target the proliferative capacity of cancer cells, which often leaves slow-proliferating, persistent cancer cells unaffected. Thus, we aimed to identify metabolic determinants that enable cell plasticity and foster treatment resistance and tumor escape. Using a panel of anti-cancer drugs, we uncovered that antifolates, despite inducing strong growth arrest, did not impact the cancer cell’s motility potential, indicating that nucleotide synthesis is dispensable for cell motility. Prolonged treatment even selected for more motile cancer subpopulations. We found that cytosolic inhibition of DHFR by MTX only abrogates cytosolic folate cycle, while mitochondrial one-carbon cycle remains highly active. Despite a decreased cellular demand for biomass production, de novo serine synthesis and formate overflow are increased, suggesting that mitochondria provide a protective environment that allows serine catabolism to support cellular motility during nucleotide synthesis inhibition. Enhanced motility of growth-arrested cells was reduced by inhibition of PHGDH-dependent de novo serine synthesis and genetic silencing of mitochondrial one-carbon cycle. In vivo targeting of mitochondrial one-carbon cycle and formate overflow strongly and significantly reduced lung metastasis formation in an orthotopic breast cancer model. In summary, we identified mitochondrial serine catabolism as a targetable, growth-independent metabolic vulnerability to limit metastatic progression.
HostingRepository	PRIDE
AnnounceDate	2022-06-09
AnnouncementXML	Submission_2022-06-09_07:12:46.342.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Gunnar Dittmar
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; formylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2021-07-07 21:45:12	ID requested
⏵ 1	2022-06-09 07:12:47	announced

Kiweler N, Delbrouck C, Pozdeev VI, Neises L, Soriano-Baguet L, Eiden K, Xian F, Benzarti M, Haase L, Koncina E, Schmoetten M, Jaeger C, Noman MZ, Vazquez A, Janji B, Dittmar G, Brenner D, Letellier E, Meiser J, Mitochondria preserve an autarkic one-carbon cycle to confer growth-independent cancer cell migration and metastasis. Nat Commun, 13(1):2699(2022) [pubmed]

submitter keyword: human, cancer, metastasis, formate

Gunnar Dittmar
contact affiliation	Luxembourg Instititute of Health
contact email	gunnar.dittmar@lih.lu
lab head
Gunnar Dittmar
contact affiliation	LIH
contact email	gunnar.dittmar@lih.lu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD027175
     1. Label: PRIDE project
     2. Name: Mitochondrial One-Carbon Flux has a Growth-Independent Role in Promoting Breast Cancer Metastasis