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

Author

Listed:
  • Mark A. Eckert

    (University of Chicago)

  • Fabian Coscia

    (Max Planck Institute of Biochemistry
    University of Copenhagen)

  • 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
    University of Copenhagen)

  • Ernst Lengyel

    (University of Chicago)

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.

Suggested Citation

  • 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 & Mari, 2019. "Proteomics reveals NNMT as a master metabolic regulator of cancer-associated fibroblasts," Nature, Nature, vol. 569(7758), pages 723-728, May.
  • Handle: RePEc:nat:nature:v:569:y:2019:i:7758:d:10.1038_s41586-019-1173-8
    DOI: 10.1038/s41586-019-1173-8
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    Cited by:

    1. Liujia Qian & Jianqing Zhu & Zhangzhi Xue & Yan Zhou & Nan Xiang & Hong Xu & Rui Sun & Wangang Gong & Xue Cai & Lu Sun & Weigang Ge & Yufeng Liu & Ying Su & Wangmin Lin & Yuecheng Zhan & Junjian Wang , 2024. "Proteomic landscape of epithelial ovarian cancer," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Yangzi Chen & Bohong Wang & Yizi Zhao & Xinxin Shao & Mingshuo Wang & Fuhai Ma & Laishou Yang & Meng Nie & Peng Jin & Ke Yao & Haibin Song & Shenghan Lou & Hang Wang & Tianshu Yang & Yantao Tian & Pen, 2024. "Metabolomic machine learning predictor for diagnosis and prognosis of gastric cancer," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    3. Yuanyuan Qu & Jinwen Feng & Xiaohui Wu & Lin Bai & Wenhao Xu & Lingli Zhu & Yang Liu & Fujiang Xu & Xuan Zhang & Guojian Yang & Jiacheng Lv & Xiuping Chen & Guo-Hai Shi & Hong-Kai Wang & Da-Long Cao &, 2022. "A proteogenomic analysis of clear cell renal cell carcinoma in a Chinese population," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    4. Simon Davis & Connor Scott & Janina Oetjen & Philip D. Charles & Benedikt M. Kessler & Olaf Ansorge & Roman Fischer, 2023. "Deep topographic proteomics of a human brain tumour," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    5. Chen Ni & Xiaohan Lou & Xiaohan Yao & Linlin Wang & Jiajia Wan & Xixi Duan & Jialu Liang & Kaili Zhang & Yuanyuan Yang & Li Zhang & Chanjun Sun & Zhenzhen Li & Ming Wang & Linyu Zhu & Dekang Lv & Zhih, 2022. "ZIP1+ fibroblasts protect lung cancer against chemotherapy via connexin-43 mediated intercellular Zn2+ transfer," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    6. Rin Mizuno & Hiroaki Hojo & Masatomo Takahashi & Soshiro Kashio & Sora Enya & Motonao Nakao & Riyo Konishi & Mayuko Yoda & Ayano Harata & Junzo Hamanishi & Hiroshi Kawamoto & Masaki Mandai & Yutaka Su, 2022. "Remote solid cancers rewire hepatic nitrogen metabolism via host nicotinamide-N-methyltransferase," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    7. Lingling Li & Dongxian Jiang & Hui Liu & Chunmei Guo & Rui Zhao & Qiao Zhang & Chen Xu & Zhaoyu Qin & Jinwen Feng & Yang Liu & Haixing Wang & Weijie Chen & Xue Zhang & Bin Li & Lin Bai & Sha Tian & Su, 2023. "Comprehensive proteogenomic characterization of early duodenal cancer reveals the carcinogenesis tracks of different subtypes," Nature Communications, Nature, vol. 14(1), pages 1-24, December.
    8. Shiyan Dong & Xuan Liu & Ye Bi & Yifan Wang & Abin Antony & DaeYong Lee & Kristin Huntoon & Seongdong Jeong & Yifan Ma & Xuefeng Li & Weiye Deng & Benjamin R. Schrank & Adam J. Grippin & JongHoon Ha &, 2023. "Adaptive design of mRNA-loaded extracellular vesicles for targeted immunotherapy of cancer," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    9. Rui Chen & Jiasu Xu & Boqian Wang & Yi Ding & Aynur Abdulla & Yiyang Li & Lai Jiang & Xianting Ding, 2024. "SpiDe-Sr: blind super-resolution network for precise cell segmentation and clustering in spatial proteomics imaging," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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