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

Mark A. Eckert, Fabian Coscia, Agnieszka Chryplewicz, Jae Won Chang, Kyle M. Hernandez, Shawn Pan, Samantha M. Tienda, Dominik A. Nahotko, Gang Li, Ivana Blaženović, Ricardo R. Lastra, Marion Curtis, S. Diane Yamada, Ruth Perets, Stephanie M. McGregor, Jorge Andrade, Oliver Fiehn, Raymond E. Moellering, Matthias Mann and Ernst Lengyel ()
Additional contact information
Mark A. Eckert: University of Chicago
Fabian Coscia: Max Planck Institute of Biochemistry
Agnieszka Chryplewicz: University of Chicago
Jae Won Chang: University of Chicago
Kyle M. Hernandez: University of Chicago
Shawn Pan: University of Chicago
Samantha M. Tienda: University of Chicago
Dominik A. Nahotko: University of Chicago
Gang Li: University of Chicago
Ivana Blaženović: University of California Davis Genome Center
Ricardo R. Lastra: University of Chicago
Marion Curtis: University of Chicago
S. Diane Yamada: University of Chicago
Ruth Perets: Clinical Research Institute at Rambam, Rambam Health Care Campus
Stephanie M. McGregor: University of Chicago
Jorge Andrade: University of Chicago
Oliver Fiehn: University of California Davis Genome Center
Raymond E. Moellering: University of Chicago
Matthias Mann: Max Planck Institute of Biochemistry
Ernst Lengyel: University of Chicago

Nature, 2019, vol. 569, issue 7758, 723-728

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1173-8

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