Metabolic heterogeneity confers differences in melanoma metastatic potential
Open accessAbstract
Metastasis requires cancer cells to undergo metabolic changes that are poorly understood 1-3. Here we show that metabolic differences among melanoma cells confer differences in metastatic potential as a result of differences in the function of the MCT1 transporter. In vivo isotope tracing analysis in patient-derived xenografts revealed differences in nutrient handling between efficiently and inefficiently metastasizing melanomas, with circulating lactate being a more prominent source of tumour lactate in efficient metastasizers. Efficient metastasizers had higher levels of MCT1, and inhibition of MCT1 reduced lactate uptake. MCT1 inhibition had little effect on the growth of primary subcutaneous tumours, but resulted in depletion of circulating melanoma cells and reduced the metastatic disease burden in patient-derived xenografts and in mouse melanomas. In addition, inhibition of MCT1 suppressed the oxidative pentose phosphate pathway and increased levels of reactive oxygen species. Antioxidants blocked the effects of MCT1 inhibition on metastasis. MCT1 high and MCT1-/low cells from the same melanomas had similar capacities to form subcutaneous tumours, but MCT1 high cells formed more metastases after intravenous injection. Metabolic differences among cancer cells thus confer differences in metastatic potential as metastasizing cells depend on MCT1 to manage oxidative stress.
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Intravenous infusion of 13C-lactate into human non-small-cell lung cancer patients and mice bearing patient-derived melanomas identified tumors with a propensity for future metastasis, which required MCT1-dependent lactate transport in the mice.
“Intravenous infusion of 13C-lactate into human non-small-cell lung cancer patients and mice bearing patient-derived melanomas identified tumors with a propensity for future metastasis, which required MCT1-dependent lactate transport in the mice (58, 100).”
From Metabolic reprogramming and cancer progression (2020) · cites this paper as [100]
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Cites
Genome engineering using the CRISPR-Cas9 system
Ran, F. A., Hsu, P. D., Wright, J., Agarwala, V., Scott, D. A., & Zhang, F. (2013) · Nature Protocols · doi:10.1038/nprot.2013.143 · Cited by 11,133 · see citing works
Understanding the Intersections between Metabolism and Cancer Biology
Heiden, M. G. V., & DeBerardinis, R. J. (2017) · Cell · doi:10.1016/j.cell.2016.12.039 · Cited by 2,316 · see citing works
Self-citationOncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis
DeNicola, G. M., Karreth, F. A., Humpton, T. J., Gopinathan, A., Wei, C., Frese, K., Mangal, D., Yu, K. H., Yeo, C. J., Calhoun, E. S., et al. (2011) · Nature · doi:10.1038/nature10189 · Cited by 2,277 · see citing works
Glucose feeds the TCA cycle via circulating lactate
Hui, S., Ghergurovich, J. M., Morscher, R. J., Jang, C., Teng, X., Lu, W., Esparza, L. A., Reya, T., Zhan, L., Yanxiang Guo, J., et al. (2017) · Nature · doi:10.1038/nature24057 · Cited by 1,721 · see citing works
Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice
Sonveaux, P., Végran, F., Schroeder, T., Wergin, M., Verrax, J., Rabbani, Z. N., Saedeleer, C. J. D., Kennedy, K. M., Diepart, C., Jordan, B. F., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci36843 · Cited by 1,635 · see citing works
Lactate Metabolism in Human Lung Tumors
Faubert, B., Li, K. Y., Cai, L., Hensley, C. T., Kim, J., Zacharias, L. G., Yang, C., Do, Q. N., Doucette, S., Burguete, D., et al. (2017) · Cell · doi:10.1016/j.cell.2017.09.019 · Cited by 1,343 · see citing works
Self-citationOxidative stress inhibits distant metastasis by human melanoma cells
Piskounova, E., Agathocleous, M., Murphy, M. M., Hu, Z., Huddlestun, S. E., Zhao, Z., Leitch, A. M., Johnson, T. M., DeBerardinis, R. J., & Morrison, S. J. (2015) · Nature · doi:10.1038/nature15726 · Cited by 1,269 · see citing works
Self-citationNoguchi, K., Gel, Y. R., Brunner, E., & Konietschke, F. (2012) · Journal of Statistical Software · doi:10.18637/jss.v050.i12 · Cited by 1,146 · see citing works
Quantitative flux analysis reveals folate-dependent NADPH production
Fan, J., Ye, J., Kamphorst, J. J., Shlomi, T., Thompson, C. B., & Rabinowitz, J. D. (2014) · Nature · doi:10.1038/nature13236 · Cited by 1,114 · see citing works
Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment
Schafer, Z. T., Grassian, A. R., Song, L., Jiang, Z., Gerhart-Hines, Z., Irie, H. Y., Gao, S., Puigserver, P., & Brugge, J. S. (2009) · Nature · doi:10.1038/nature08268 · Cited by 1,031 · see citing works
Harris, I. S., Treloar, A. E., Inoue, S., Sasaki, M., Gorrini, C., Lee, K. C., Yung, K. Y., Brenner, D., Knobbe-Thomsen, C. B., Cox, M. A., et al. (2015) · Cancer Cell · doi:10.1016/j.ccell.2014.11.019 · Cited by 993 · see citing works
Antioxidants Accelerate Lung Cancer Progression in Mice
Sayin, V. I., Ibrahim, M. X., Larsson, E., Nilsson, J. A., Lindahl, P., & Bergo, M. O. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3007653 · Cited by 867 · see citing works
Metabolomics and Isotope Tracing
Jang, C., Chen, L., & Rabinowitz, J. D. (2018) · Cell · doi:10.1016/j.cell.2018.03.055 · Cited by 841 · see citing works
Matsuyama, S., Llopis, J. L., Deveraux, Q. L., Tsien, R. Y., & Reed, J. C. (2000) · Nature Cell Biology · doi:10.1038/35014006 · Cited by 740 · see citing works
Kirk, P. B., Wilson, M. C., Heddle, C., Brown, M. H., Barclay, A. N., & Halestrap, A. P. (2000) · The EMBO Journal · doi:10.1093/emboj/19.15.3896 · Cited by 703 · see citing works
Yang, C., Ko, B., Hensley, C. T., Jiang, L., Wasti, A. T., Kim, J., Sudderth, J., Calvaruso, M. A., Lumata, L., Mitsche, M., et al. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.09.025 · Cited by 679 · see citing works
Self-citationAntioxidants can increase melanoma metastasis in mice
Le Gal, K., Ibrahim, M. X., Wiel, C., Sayin, V. I., Akula, M. K., Karlsson, C., Dalin, M. G., Akyürek, L. M., Lindahl, P., Nilsson, J., et al. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aad3740 · Cited by 632 · see citing works
The Two Faces of Reactive Oxygen Species in Cancer
Reczek, C. R., & Chandel, N. S. (2017) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-041916-065808 · Cited by 602 · see citing works
Vanharanta, S., & Massagué, J. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.09.007 · Cited by 563 · see citing works
Tracing compartmentalized NADPH metabolism in the cytosol and mitochondria of mammalian cells
Lewis, C. A., Parker, S. J., Fiske, B. P., McCloskey, D., Gui, D. Y., Green, C. R., Vokes, N. I., Feist, A. M., Vander Heiden, M. G., & Metallo, C. M. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.05.008 · Cited by 562 · see citing works
Feron, O. (2009) · Radiotherapy and Oncology · doi:10.1016/j.radonc.2009.06.025 · Cited by 559 · see citing works
Marin-Valencia, I., Yang, C., Mashimo, T., Cho, S., Baek, H., Yang, X.-L., Rajagopalan, K. N., Maddie, M., Vemireddy, V., Zhao, Z., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.05.001 · Cited by 529 · see citing works
Self-citationDoherty, J. R., Yang, C., Scott, K. E. N., Cameron, M. D., Fallahi, M., Li, W., Hall, M. A., Amelio, A. L., Mishra, J. K., Li, F., et al. (2013) · Cancer Research · doi:10.1158/0008-5472.can-13-2034 · Cited by 399 · see citing works
Halestrap, A. P. (2013) · Comprehensive physiology · doi:10.1002/cphy.c130008 · Cited by 389 · see citing works
Activity of the Monocarboxylate Transporter 1 Inhibitor AZD3965 in Small Cell Lung Cancer
Polański, R., Hodgkinson, C. L., Fusi, A., Nonaka, D., Priest, L., Kelly, P., Trapani, F., Bishop, P. W., White, A., Critchlow, S. E., et al. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-2270 · Cited by 378 · see citing works
Targeting Breast Cancer Stem Cell State Equilibrium through Modulation of Redox Signaling
Luo, M., Li, S., Brooks, M. D., Jiagge, E. M., Zhu, Y., Buschhaus, J. M., Conley, S. J., Fath, M. A., Davis, A., Gheordunescu, E., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.06.006 · Cited by 354 · see citing works
The YUMM lines: a series of congenic mouse melanoma cell lines with defined genetic alterations
Meeth, K. M., Wang, J. X., Micevic, G., Damsky, W., & Bosenberg, M. (2016) · Pigment Cell & Melanoma Research · doi:10.1111/pcmr.12498 · Cited by 330 · see citing works
Lactate metabolism is associated with mammalian mitochondria
Chen, Y.-J., Mahieu, N. G., Huang, X., Singh, M., Crawford, P. A., Johnson, S. L., Gross, R. W., Schaefer, J., & Patti, G. J. (2016) · Nature Chemical Biology · doi:10.1038/nchembio.2172 · Cited by 326 · see citing works
Metabolite Spectral Accuracy on Orbitraps
Su, X., Lu, W., & Rabinowitz, J. D. (2017) · Analytical Chemistry · doi:10.1021/acs.analchem.7b00396 · Cited by 270 · see citing works
Cyclic changes in metabolic state during the life of a yeast cell
Tu, B. P., Mohler, R. E., Liu, J. C., Dombek, K. M., Young, E. T., Synovec, R. E., & McKnight, S. L. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0708365104 · Cited by 260 · see citing works
Transketolase counteracts oxidative stress to drive cancer development
Xu, I. M.-J., Lai, R. K.-H., Lin, S.-H., Tse, A. P.-W., Chiu, D. K.-C., Koh, H.-Y., Law, C.-T., Wong, C.-M., Cai, Z., Wong, C. C.-L., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1508779113 · Cited by 251 · see citing works
MCT1 Modulates Cancer Cell Pyruvate Export and Growth of Tumors that Co-express MCT1 and MCT4
Hong, C. S., Graham, N. A., Gu, W., Camacho, C. E., Mah, V. H., Maresh, E. L., Alavi, M., Bagryanova, L., Krotee, P., Gardner, B. K., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.01.057 · Cited by 223 · see citing works
Self-citationBaek, G., Tse, Y. F., Hu, Z., Cox, D., Buboltz, N., McCue, P. A., Yeo, C. J., White, M. A., DeBerardinis, R. J., Knudsen, E. S., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.11.025 · Cited by 221 · see citing works
Self-citationIzumi, H., Takahashi, M., Uramoto, H., Nakayama, Y., Oyama, T., Wang, K., Sasaguri, Y., Nishizawa, S., & Kohno, K. (2011) · Cancer Science · doi:10.1111/j.1349-7006.2011.01908.x · Cited by 180 · see citing works
Curtis, N. J., Mooney, L. M., Hopcroft, L., Michopoulos, F., Whalley, N., Zhong, H., Murray, C. M., Logié, A., Revill, M., Byth, K. F., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.18215 · Cited by 172 · see citing works
Glucose 6-Phosphate Dehydrogenase from Human Erythrocytes
Kirkman, H. N., & Hendrickson, E. M. (1962) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)63447-2 · Cited by 143 · see citing works
Payen, V. L., Hsu, M. Y., Rädecke, K. S., Wyart, E., Vazeille, T., Bouzin, C., Porporato, P. E., & Sonveaux, P. (2017) · Cancer Research · doi:10.1158/0008-5472.can-17-0764 · Cited by 120 · see citing works
Human Melanoma Metastasis in NSG Mice Correlates with Clinical Outcome in Patients
Quintana, E., Piskounova, E., Shackleton, M. J., Weinberg, D. N., Eskiocak, U., Fullen, D. R., Johnson, T. M., & Morrison, S. J. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3004599 · Cited by 108 · see citing works
Self-citationGuan, X., Rodriguez‐Cruz, V., & Morris, M. E. (2019) · The AAPS Journal · doi:10.1208/s12248-018-0279-5 · Cited by 108 · see citing works
The metabolic microenvironment of melanomas: Prognostic value of MCT1 and MCT4
Pinheiro, C. M., Miranda‐Gonçalves, V., Longatto‐Filho, A., Vicente, A. L. S. A., Berardinelli, G. N., Scapulatempo‐Neto, C., Costa, R. F. A., Viana, C. R., Reis, R. M., Baltazar, F., et al. (2016) · Cell Cycle · doi:10.1080/15384101.2016.1175258 · Cited by 88 · see citing works
Shi, X., Tasdogan, A., Huang, F., Hu, Z., Morrison, S. J., & DeBerardinis, R. J. (2017) · Science Advances · doi:10.1126/sciadv.aao5268 · Cited by 47 · see citing works
Self-citationAMPK promotes survival of c‐Myc‐positive melanoma cells by suppressing oxidative stress
Kfoury, A., Armaro, M., Collodet, C., Sordet‐Dessimoz, J., Giner, M. P., Christen, S., Moco, S., Leleu, M., de Leval, L., Koch, U., et al. (2018) · The EMBO Journal · doi:10.15252/embj.201797673 · Cited by 39 · see citing works
Andrés, V., Carreras, J., & Cussó, R. (1990) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(05)80213-x · Cited by 31 · see citing works
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- Authors
- Tasdogan, A., Faubert, B., Ramesh, V., Ubellacker, J. M., Shen, B., Solmonson, A., Murphy, M. M., Gu, Z., Gu, W., Martin, M., Kasitinon, S. Y., Vandergriff, T., Mathews, T. P., Zhao, Z., Schadendorf, D., DeBerardinis, R. J., & Morrison, S. J.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- Howard Hughes Medical Institute (US)
- Corresponding author
- DeBerardinis, Ralph J.
- Morrison, Sean J.
- ORCID
- Venue
- Nature
- Published
- 2019-12-18
- Volume
- 577
- Issue
- 7788
- Pages
- 115-120
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6930341
- OpenAlex
- W2995147378
- Cited by
- 509
- References
- 43
- Citations by year
- 2026: 48 · 2025: 87 · 2024: 82 · 2023: 78 · 2022: 86 · 2021: 67 · 2020: 61
- FWCI
- 16.88
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Heart, Lung, and Blood Institute (F32HL139016)
- National Cancer Institute (U01CA228608, R35CA220449)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (F32HD096786)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- melanoma, metastasis, MCT1, lactate utilization, oxidative pentose phosphate pathway, reactive oxygen species, oxidative stress resistance, metabolic heterogeneity, patient-derived xenografts, isotope tracing, MCT1 inhibition, tumour cell dissemination
- MeSH terms
- Monocarboxylate Transport Protein 1, Animals, Cell Survival, Humans, Melanoma, Oxidative Stress, Xenograft Model Antitumor Assays, Monocarboxylic Acid Transporters, Symporters, Cell Line, Tumor, Mice
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