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

被引：357

作者：

Eckert, Mark A. ^{[1
]}

Coscia, Fabian ^{[2
,3
]}

Chryplewicz, Agnieszka ^{[1
]}

Chang, Jae Won ^{[4
]}

Hernandez, Kyle M. ^{[5
]}

Pan, Shawn ^{[1
]}

Tienda, Samantha M. ^{[1
]}

Nahotko, Dominik A. ^{[1
]}

Li, Gang ^{[4
]}

Blazenovic, Ivana ^{[6
]}

Lastra, Ricardo R. ^{[7
]}

Curtis, Marion ^{[1
]}

Yamada, S. Diane ^{[1
]}

Perets, Ruth ^{[8
]}

McGregor, Stephanie M. ^{[7
]}

Andrade, Jorge ^{[5
]}

Fiehn, Oliver ^{[6
]}

Moellering, Raymond E. ^{[4
]}

Mann, Matthias ^{[2
,3
]}

Lengyel, Ernst ^{[1
]}

机构：

[1] Univ Chicago, Dept Obstet & Gynecol, Gynecol Oncol Sect, Chicago, IL 60637 USA

[2] Max Planck Inst Biochem, Dept Prote & Signal Transduct, Martinsried, Germany

[3] Univ Copenhagen, Clin Prote Grp, Prote Program, Novo Nordisk Fdn Ctr Prot Res, Copenhagen, Denmark

[4] Univ Chicago, Dept Chem, 5735 S Ellis Ave, Chicago, IL 60637 USA

[5] Univ Chicago, Ctr Res Informat, Chicago, IL 60637 USA

[6] Univ Calif Davis, West Coast Metabol Ctr, Genome Ctr, Davis, CA 95616 USA

[7] Univ Chicago, Dept Pathol, 5841 S Maryland Ave, Chicago, IL 60637 USA

[8] Rambam Hlth Care Campus, Div Oncol, Clin Res Inst Rambam, Haifa, Israel

来源：

NATURE | 2019年 / 569卷 / 7758期

关键词：

NICOTINAMIDE N-METHYLTRANSFERASE; OVARIAN-CANCER; METASTASIS; CELLS; IDENTIFICATION; PROGRESSION; LIPIDOMICS; SIGNATURES; CARCINOMA;

D O I：

10.1038/s41586-019-1173-8

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：723 / +

页数：24

共 52 条

[1] Mass-spectrometric exploration of proteome structure and function [J].

Aebersold, Ruedi ;

Mann, Matthias .

NATURE, 2016, 537 (7620) :347-355

[2]

AKSOY S, 1994, J BIOL CHEM, V269, P14835

[3] Signatures of mutational processes in human cancer [J].

Alexandrov, Ludmil B. ;

Nik-Zainal, Serena ;

Wedge, David C. ;

Aparicio, Samuel A. J. R. ;

Behjati, Sam ;

Biankin, Andrew V. ;

Bignell, Graham R. ;

Bolli, Niccolo ;

Borg, Ake ;

Borresen-Dale, Anne-Lise ;

Boyault, Sandrine ;

Burkhardt, Birgit ;

Butler, Adam P. ;

Caldas, Carlos ;

Davies, Helen R. ;

Desmedt, Christine ;

Eils, Roland ;

Eyfjord, Jorunn Erla ;

Foekens, John A. ;

Greaves, Mel ;

Hosoda, Fumie ;

Hutter, Barbara ;

Ilicic, Tomislav ;

Imbeaud, Sandrine ;

Imielinsk, Marcin ;

Jaeger, Natalie ;

Jones, David T. W. ;

Jones, David ;

Knappskog, Stian ;

Kool, Marcel ;

Lakhani, Sunil R. ;

Lopez-Otin, Carlos ;

Martin, Sancha ;

Munshi, Nikhil C. ;

Nakamura, Hiromi ;

Northcott, Paul A. ;

Pajic, Marina ;

Papaemmanuil, Elli ;

Paradiso, Angelo ;

Pearson, John V. ;

Puente, Xose S. ;

Raine, Keiran ;

Ramakrishna, Manasa ;

Richardson, Andrea L. ;

Richter, Julia ;

Rosenstiel, Philip ;

Schlesner, Matthias ;

Schumacher, Ton N. ;

Span, Paul N. ;

Teague, Jon W. .

NATURE, 2013, 500 (7463) :415-+

[4] Differential peak calling of ChIP-seq signals with replicates with THOR [J].

Allhoff, Manuel ;

Sere, Kristin ;

Pires, Juliana F. ;

Zenke, Martin ;

Costa, Ivan G. .

NUCLEIC ACIDS RESEARCH, 2016, 44 (20) :e153

[5] Trends in ultrasensitive proteomics [J].

Altelaar, A. F. Maarten ;

Heck, Albert J. R. .

CURRENT OPINION IN CHEMICAL BIOLOGY, 2012, 16 (1-2) :206-213

[6] Integrated genomic analyses of ovarian carcinoma [J].

Bell, D. ;

Berchuck, A. ;

Birrer, M. ;

Chien, J. ;

Cramer, D. W. ;

Dao, F. ;

Dhir, R. ;

DiSaia, P. ;

Gabra, H. ;

Glenn, P. ;

Godwin, A. K. ;

Gross, J. ;

Hartmann, L. ;

Huang, M. ;

Huntsman, D. G. ;

Iacocca, M. ;

Imielinski, M. ;

Kalloger, S. ;

Karlan, B. Y. ;

Levine, D. A. ;

Mills, G. B. ;

Morrison, C. ;

Mutch, D. ;

Olvera, N. ;

Orsulic, S. ;

Park, K. ;

Petrelli, N. ;

Rabeno, B. ;

Rader, J. S. ;

Sikic, B. I. ;

Smith-McCune, K. ;

Sood, A. K. ;

Bowtell, D. ;

Penny, R. ;

Testa, J. R. ;

Chang, K. ;

Dinh, H. H. ;

Drummond, J. A. ;

Fowler, G. ;

Gunaratne, P. ;

Hawes, A. C. ;

Kovar, C. L. ;

Lewis, L. R. ;

Morgan, M. B. ;

Newsham, I. F. ;

Santibanez, J. ;

Reid, J. G. ;

Trevino, L. R. ;

Wu, Y. -Q. ;

Wang, M. .

NATURE, 2011, 474 (7353) :609-615

[7] Validating Quantitative Untargeted Lipidomics Across Nine Liquid Chromatography-High-Resolution Mass Spectrometry Platforms [J].

Cajka, Tomas ;

Smilowitz, Jennifer T. ;

Fiehn, Oliver .

ANALYTICAL CHEMISTRY, 2017, 89 (22) :12360-12368

[8]

Cajka T, 2017, METHODS MOL BIOL, V1609, P149, DOI 10.1007/978-1-4939-6996-8_14

[9] Profiling Reactive Metabolites via Chemical Trapping and Targeted Mass Spectrometry [J].

Chang, Jae Won ;

Lee, Gihoon ;

Coukos, John S. ;

Moellering, Raymond E. .

ANALYTICAL CHEMISTRY, 2016, 88 (13) :6658-6661

[10] Integrative proteomic profiling of ovarian cancer cell lines reveals precursor cell associated proteins and functional status [J].

Coscia, F. ;

Watters, K. M. ;

Curtis, M. ;

Eckert, M. A. ;

Chiang, C. Y. ;

Tyanova, S. ;

Montag, A. ;

Lastra, R. R. ;

Lengyel, E. ;

Mann, M. .

NATURE COMMUNICATIONS, 2016, 7

← 1 2 3 4 5 6 →