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

Item Type:Article
Title:Proteomics reveals NNMT as a master metabolic regulator of cancer-associated fibroblasts
Creators Name:Eckert, M.A. and Coscia, F. and Chryplewicz, A. and Chang, J.W. and Hernandez, K.M. and Pan, S. and Tienda, S.M. and Nahotko, D.A. and Li, G. and Blaženović, I. and Lastra, R.R. and Curtis, M. and Yamada, S.D. and Perets, R. and McGregor, S.M. and Andrade, J. and Fiehn, O. and Moellering, R.E. and Mann, M. and Lengyel, E.
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, 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.
Keywords:Cancer-Associated Fibroblasts, Cultured Cells, Disease Progression, DNA Methylation, Histones, Neoplasm Metastasis, Niacinamide, Nicotinamide N-Methyltransferase, Ovarian Neoplasms, Phenotype, Prognosis, Proteomics, S-Adenosylhomocysteine, S-Adenosylmethionine, Tumor Cell Line
Publisher:Nature Publishing Group
Page Range:723-728
Date:30 May 2019
Official Publication:https://doi.org/10.1038/s41586-019-1173-8
PubMed:View item in PubMed

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