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Nature. 2019 May;569(7758):723-728. doi: 10.1038/s41586-019-1173-8. Epub 2019 May 1.

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

Author information

1
Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, Chicago, IL, USA.
2
Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany.
3
Clinical Proteomics Group, Proteomics Program, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.
4
Department of Chemistry, University of Chicago, Chicago, IL, USA.
5
Center for Research Informatics, University of Chicago, Chicago, IL, USA.
6
West Coast Metabolomics Center, University of California Davis Genome Center, Davis, CA, USA.
7
Department of Pathology, University of Chicago, Chicago, IL, USA.
8
Division of Oncology, Clinical Research Institute at Rambam, Rambam Health Care Campus, Haifa, Israel.
9
Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, Chicago, IL, USA. elengyel@uchicago.edu.

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 cancer1,2, 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.

PMID:
31043742
DOI:
10.1038/s41586-019-1173-8

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