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  Proteomics reveals NNMT as a master metabolic regulator of cancer-associated fibroblasts

Eckert, M. A., Coscia, F., Chryplewicz, A., Chang, J. W., Hernandez, K. M., Pan, S., et al. (2019). Proteomics reveals NNMT as a master metabolic regulator of cancer-associated fibroblasts. Nature, 569(7758), 723-728. doi:10.1038/s41586-019-1173-8.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-E783-4 Version Permalink: http://hdl.handle.net/21.11116/0000-0003-E784-3
Genre: Journal Article

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 Creators:
Eckert, Mark A.1, Author
Coscia, Fabian2, Author              
Chryplewicz, Agnieszka1, Author
Chang, Jae Won1, Author
Hernandez, Kyle M.1, Author
Pan, Shawn1, Author
Tienda, Samantha M.1, Author
Nahotko, Dominik A.1, Author
Li, Gang1, Author
Blazenovic, Ivana1, Author
Lastra, Ricardo R.1, Author
Curtis, Marion1, Author
Yamada, S. Diane1, Author
Perets, Ruth1, Author
McGregor, Stephanie M.1, Author
Andrade, Jorge1, Author
Fiehn, Oliver1, Author
Moellering, Raymond E.1, Author
Mann, Matthias2, Author              
Lengyel, Ernst1, Author
Affiliations:
1external, ou_persistent22              
2Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              

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Free keywords: NICOTINAMIDE N-METHYLTRANSFERASE; OVARIAN-CANCER; METASTASIS; CELLS; IDENTIFICATION; PROGRESSION; LIPIDOMICS; SIGNATURES; CARCINOMAScience & Technology - Other Topics;
 Abstract: High-grade serous carcinoma has a poor prognosis, owing primarily to its early dissemination throughout the abdominal cavity. Genomic and proteomic approaches have provided snapshots of the proteogenomics of ovarian cancer(1,2), but a systematic examination of both the tumour and stromal compartments is critical in understanding ovarian cancer metastasis. Here we develop a label-free proteomic workflow to analyse as few as 5,000 formalin-fixed, paraffin-embedded cells microdissected from each compartment. The tumour proteome was stable during progression from in situ lesions to metastatic disease; however, the metastasis-associated stroma was characterized by a highly conserved proteomic signature, prominently including the methyltransferase nicotinamide N-methyltransferase (NNMT) and several of the proteins that it regulates. Stromal NNMT expression was necessary and sufficient for functional aspects of the cancer-associated fibroblast (CAF) phenotype, including the expression of CAF markers and the secretion of cytokines and oncogenic extracellular matrix. Stromal NNMT expression supported ovarian cancer migration, proliferation and in vivo growth and metastasis. Expression of NNMT in CAFs led to depletion of S-adenosyl methionine and reduction in histone methylation associated with widespread gene expression changes in the tumour stroma. This work supports the use of ultra-low-input proteomics to identify candidate drivers of disease phenotypes. NNMT is a central, metabolic regulator of CAF differentiation and cancer progression in the stroma that may be therapeutically targeted.

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Language(s): eng - English
 Dates: 2019
 Publication Status: Published in print
 Pages: 24
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: ISI: 000470144100045
DOI: 10.1038/s41586-019-1173-8
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Title: Nature
  Abbreviation : Nature
Source Genre: Journal
 Creator(s):
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 569 (7758) Sequence Number: - Start / End Page: 723 - 728 Identifier: ISSN: 0028-0836
CoNE: https://pure.mpg.de/cone/journals/resource/954925427238