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Article

Systematic Identification of MACC1-Driven Metabolic Networks in Colorectal Cancer

1
Medical Department of Hematology, Oncology, and Tumor Immunology, and Molekulares Krebsforschungszentrum (MKFZ), Chariteé–Universitaätsmedizin Berlin, 13353 Berlin, Germany
2
German Cancer Consortium, Deutsches Krebsforschungzentrum (DKFZ), 69120 Heidelberg, Germany
3
Department 1.7 Analytical Chemistry, Federal Institute for Materials Research and Testing (BAM), 12489 Berlin, Germany
4
Experimental and Clinical Research Center, Charité–Universitätsmedizin Berlin, and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Translational Oncology of Solid Tumors, 13125 Berlin, Germany
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Department of Hepatology and Gastroenterology, Charité–Universitätsmedizin Berlin, 13353 Berlin, Germany
6
Hasso Plattner Institute, Digital Engineering Faculty, University of Potsdam, 14482 Potsdam, Germany
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Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Mathematical Modeling of Cellular Processes, 13125 Berlin, Germany
8
Berlin Experimental Radionuclide Imaging Center (BERIC), Charité–Universitätsmedizin Berlin, 13353 Berlin, Germany
9
Department of Nuclear Medicine, Charité–Universitätsmedizin Berlin, 13353 Berlin, Germany
*
Author to whom correspondence should be addressed.
Academic Editors: Thomas M. O’Connell and Wei Jia
Cancers 2021, 13(5), 978; https://doi.org/10.3390/cancers13050978
Received: 11 December 2020 / Revised: 16 February 2021 / Accepted: 21 February 2021 / Published: 26 February 2021
(This article belongs to the Special Issue Insights into Cancer Metabolism from Metabolomics)
We aimed at the systematic identification of MACC1-driven metabolic networks in colorectal cancer. By this systematic analysis, our studies revealed new insights into MACC1-caused metabolomics phenotypes: (i) MACC1 fosters metastasis by rewiring glucose and glutamine metabolism, (ii) MACC1 increases glucose use by enhanced surface GLUT1; (iii) MACC1 increases glutamine and pyruvate use by enhanced uptake, and (iv) MACC1 reduces glutamine flux but has minor effects on pyruvate flux. Therefore, MACC1 is an important regulator of cancer metabolism.
MACC1 is a prognostic and predictive metastasis biomarker for more than 20 solid cancer entities. However, its role in cancer metabolism is not sufficiently explored. Here, we report on how MACC1 impacts the use of glucose, glutamine, lactate, pyruvate and fatty acids and show the comprehensive analysis of MACC1-driven metabolic networks. We analyzed concentration-dependent changes in nutrient use, nutrient depletion, metabolic tracing employing 13C-labeled substrates, and in vivo studies. We found that MACC1 permits numerous effects on cancer metabolism. Most of those effects increased nutrient uptake. Furthermore, MACC1 alters metabolic pathways by affecting metabolite production or turnover from metabolic substrates. MACC1 supports use of glucose, glutamine and pyruvate via their increased depletion or altered distribution within metabolic pathways. In summary, we demonstrate that MACC1 is an important regulator of metabolism in cancer cells. View Full-Text
Keywords: MACC1; cancer metabolism; metabolic profiling; metabolic networks; colorectal cancer MACC1; cancer metabolism; metabolic profiling; metabolic networks; colorectal cancer
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MDPI and ACS Style

Lisec, J.; Kobelt, D.; Walther, W.; Mokrizkij, M.; Grötzinger, C.; Jaeger, C.; Baum, K.; Simon, M.; Wolf, J.; Beindorff, N.; Brenner, W.; Stein, U. Systematic Identification of MACC1-Driven Metabolic Networks in Colorectal Cancer. Cancers 2021, 13, 978. https://doi.org/10.3390/cancers13050978

AMA Style

Lisec J, Kobelt D, Walther W, Mokrizkij M, Grötzinger C, Jaeger C, Baum K, Simon M, Wolf J, Beindorff N, Brenner W, Stein U. Systematic Identification of MACC1-Driven Metabolic Networks in Colorectal Cancer. Cancers. 2021; 13(5):978. https://doi.org/10.3390/cancers13050978

Chicago/Turabian Style

Lisec, Jan, Dennis Kobelt, Wolfgang Walther, Margarita Mokrizkij, Carsten Grötzinger, Carsten Jaeger, Katharina Baum, Mareike Simon, Jana Wolf, Nicola Beindorff, Winfried Brenner, and Ulrike Stein. 2021. "Systematic Identification of MACC1-Driven Metabolic Networks in Colorectal Cancer" Cancers 13, no. 5: 978. https://doi.org/10.3390/cancers13050978

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