Stress-induced epinephrine enhances lactate dehydrogenase A and promotes breast cancer stem-like cells

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Abstract

Chronic stress triggers activation of the sympathetic nervous system and drives malignancy. Using an immunodeficient murine system, we showed that chronic stress–induced epinephrine promoted breast cancer stem-like properties via lactate dehydrogenase A–dependent (LDHA-dependent) metabolic rewiring. Chronic stress–induced epinephrine activated LDHA to generate lactate, and the adjusted pH directed USP28-mediated deubiquitination and stabilization of MYC. The SLUG promoter was then activated by MYC, which promoted development of breast cancer stem-like traits. Using a drug screen that targeted LDHA, we found that a chronic stress–induced cancer stem-like phenotype could be reversed by vitamin C. These findings demonstrated the critical importance of psychological factors in promoting stem-like properties in breast cancer cells. Thus, the LDHA-lowering agent vitamin C can be a potential approach for combating stress-associated breast cancer.

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LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells.

Almut Brand, Katrin Singer, Gudrun Koehl … (2016)

Elevated lactate dehydrogenase A (LDHA) expression is associated with poor outcome in tumor patients. Here we show that LDHA-associated lactic acid accumulation in melanomas inhibits tumor surveillance by T and NK cells. In immunocompetent C57BL/6 mice, tumors with reduced lactic acid production (Ldha(low)) developed significantly slower than control tumors and showed increased infiltration with IFN-γ-producing T and NK cells. However, in Rag2(-/-)γc(-/-) mice, lacking lymphocytes and NK cells, and in Ifng(-/-) mice, Ldha(low) and control cells formed tumors at similar rates. Pathophysiological concentrations of lactic acid prevented upregulation of nuclear factor of activated T cells (NFAT) in T and NK cells, resulting in diminished IFN-γ production. Database analyses revealed negative correlations between LDHA expression and T cell activation markers in human melanoma patients. Our results demonstrate that lactic acid is a potent inhibitor of function and survival of T and NK cells leading to tumor immune escape.

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MYC/PGC-1α Balance Determines the Metabolic Phenotype and Plasticity of Pancreatic Cancer Stem Cells.

Patricia Sancho, Emma Burgos-Ramos, Alejandra Tavera … (2015)

The anti-diabetic drug metformin targets pancreatic cancer stem cells (CSCs), but not their differentiated progenies (non-CSCs), which may be related to distinct metabolic phenotypes. Here we conclusively demonstrate that while non-CSCs were highly glycolytic, CSCs were dependent on oxidative metabolism (OXPHOS) with very limited metabolic plasticity. Thus, mitochondrial inhibition, e.g., by metformin, translated into energy crisis and apoptosis. However, resistant CSC clones eventually emerged during treatment with metformin due to their intermediate glycolytic/respiratory phenotype. Mechanistically, suppression of MYC and subsequent increase of PGC-1α were identified as key determinants for the OXPHOS dependency of CSCs, which was abolished in resistant CSC clones. Intriguingly, no resistance was observed for the mitochondrial ROS inducer menadione and resistance could also be prevented/reversed for metformin by genetic/pharmacological inhibition of MYC. Thus, the specific metabolic features of pancreatic CSCs are amendable to therapeutic intervention and could provide the basis for developing more effective therapies to combat this lethal cancer.

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Haematopoietic stem and progenitor cells from human pluripotent stem cells

Ryohichi Sugimura, Deepak Jha, Areum Han … (2017)

A variety of tissue lineages can be differentiated from pluripotent stem cells by mimicking embryonic development through stepwise exposure to morphogens, or by conversion of one differentiated cell type into another by enforced expression of master transcription factors. Here, to yield functional human haematopoietic stem cells, we perform morphogen-directed differentiation of human pluripotent stem cells into haemogenic endothelium followed by screening of 26 candidate haematopoietic stem-cell-specifying transcription factors for their capacity to promote multi-lineage haematopoietic engraftment in mouse hosts. We recover seven transcription factors (ERG, HOXA5, HOXA9, HOXA10, LCOR, RUNX1 and SPI1) that are sufficient to convert haemogenic endothelium into haematopoietic stem and progenitor cells that engraft myeloid, B and T cells in primary and secondary mouse recipients. Our combined approach of morphogen-driven differentiation and transcription-factor-mediated cell fate conversion produces haematopoietic stem and progenitor cells from pluripotent stem cells and holds promise for modelling haematopoietic disease in humanized mice and for therapeutic strategies in genetic blood disorders.

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Author and article information

Contributors

Bai Cui

Yuanyuan Luo:

ORCID: http://orcid.org/0000-0002-3826-3637

Pengfei Tian

Fei Peng:

ORCID: http://orcid.org/0000-0003-0772-0273

Jinxin Lu

Yongliang Yang

Qitong Su

Bing Liu

Jiachuan Yu

Xi Luo

Liu Yin

Wei Cheng

Fan An

Bin He

Dapeng Liang

Sijin Wu:

ORCID: http://orcid.org/0000-0003-4554-4610

Peng Chu

Luyao Song

Xinyu Liu

Huandong Luo

Jie Xu

Yujia Pan

Yang Wang

Dangsheng Li

Peng Huang

Qingkai Yang

Lingqiang Zhang

Binhua P. Zhou

Suling Liu

Guowang Xu

Keith W. Kelley:

ORCID: http://orcid.org/0000-0002-6837-8793

Quentin Liu

Journal

Journal ID (nlm-ta): J Clin Invest

Journal ID (iso-abbrev): J. Clin. Invest

Journal ID (publisher-id): J Clin Invest

Title: The Journal of Clinical Investigation

Publisher: American Society for Clinical Investigation

ISSN (Print): 0021-9738

ISSN (Electronic): 1558-8238

Publication date (Electronic, pub): 28 January 2019

Publication date (Electronic, collection): 28 January 2019

Publication date (Print, pub): 1 March 2019

Publication date PMC-release: 1 March 2019

Volume: 129

Issue: 3

Pages: 1030-1046

Affiliations

[1 ]Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.

[2 ]State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.

[3 ]CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.

[4 ]Center for Molecular Medicine, School of Life Science and Biotechnology, Dalian University of Technology, Dalian, China.

[5 ]Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.

[6 ]Shanghai Information Center for Life Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

[7 ]State Key Laboratory of Proteomics, National Center of Protein Sciences, Beijing Institute of Lifeomics, Beijing, China.

[8 ]Department of Molecular and Cellular Biochemistry, Markey Cancer Center, University of Kentucky, College of Medicine, Lexington, Kentucky, USA.

[9 ]Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai, China.

[10 ]Department of Surgery and Cancer, Imperial College London, London, United Kingdom.

[11 ]Laboratory of Immunophysiology, Department of Animal Sciences, College of Agricultural, Consumer and Environmental Sciences, and Department of Pathology, College of Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.

Author notes

Address correspondence to: Quentin Liu, Institute of Cancer Stem Cell, Dalian Medical University, 9 Western Section, Lvshun South Street, Lvshunkou District, Dalian, Liaoning 116044, China. Phone: 86.411.86110508; Email: liuq9@ 123456mail.sysu.edu.cn .

Authorship note: BC, YL, PT, FP, JL, and YY contributed equally to this work.

Author information

Yuanyuan Luo http://orcid.org/0000-0002-3826-3637

Fei Peng http://orcid.org/0000-0003-0772-0273

Sijin Wu http://orcid.org/0000-0003-4554-4610

Keith W. Kelley http://orcid.org/0000-0002-6837-8793

Article

Publisher ID: 121685

DOI: 10.1172/JCI121685

PMC ID: 6391112

PubMed ID: 30688660

SO-VID: 8ccd871d-ad05-4cd5-995d-0e71f097c767

License:

This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 19 April 2018

Date accepted : 30 November 2018

Funding

Funded by: National Natural Science Foundation of China, https://doi.org/10.13039/501100001809;

Award ID: 81573025

Funded by: Dalian high-level talent innovation program

Award ID: 2016RD12

Funded by: National Natural Science Foundation of China

Award ID: 81630005

Funded by: Innovative Research Team in University of Ministry of Education of China

Award ID: IRT_17R15

Funded by: National Natural Science Foundation of China, https://doi.org/10.13039/501100001809;

Award ID: 81402445,81402071,81502579,81502594,81602585,81703062,81703091

Funded by: Innovative Research Team in University of Liaoning

Award ID: LT2017001

Funded by: Liaoning Science Fund for Young Scholars

Award ID: 5061137

Funded by: International Scientific and Technological Cooperation of Dalian

Award ID: 2015F11GH095

Funded by: MRC

Award ID: MR/N012097/1

Funded by: CRUK

Award ID: C37/A12011,C37/A18784

Funded by: Breast Cancer Now, https://doi.org/10.13039/100009794;

Award ID: 2012MayPR070,2012NovPhD016

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Stress-induced epinephrine enhances lactate dehydrogenase A and promotes breast cancer stem-like cells

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Karger: Oncology

Most cited references 54

LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells.

MYC/PGC-1α Balance Determines the Metabolic Phenotype and Plasticity of Pancreatic Cancer Stem Cells.

Haematopoietic stem and progenitor cells from human pluripotent stem cells

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