PMID- 35815941
OWN - NLM
STAT- MEDLINE
DCOM- 20220728
LR  - 20240102
IS  - 2050-084X (Electronic)
IS  - 2050-084X (Linking)
VI  - 11
DP  - 2022 Jul 11
TI  - Metabolic requirement for GOT2 in pancreatic cancer depends on environmental 
      context.
LID - 10.7554/eLife.73245 [doi]
LID - e73245
AB  - Mitochondrial glutamate-oxaloacetate transaminase 2 (GOT2) is part of the 
      malate-aspartate shuttle, a mechanism by which cells transfer reducing 
      equivalents from the cytosol to the mitochondria. GOT2 is a key component of 
      mutant KRAS (KRAS*)-mediated rewiring of glutamine metabolism in pancreatic 
      ductal adenocarcinoma (PDA). Here, we demonstrate that the loss of GOT2 disturbs 
      redox homeostasis and halts proliferation of PDA cells in vitro. GOT2 knockdown 
      (KD) in PDA cell lines in vitro induced NADH accumulation, decreased Asp and 
      alpha-ketoglutarate (alphaKG) production, stalled glycolysis, disrupted the TCA cycle, 
      and impaired proliferation. Oxidizing NADH through chemical or genetic means 
      resolved the redox imbalance induced by GOT2 KD, permitting sustained 
      proliferation. Despite a strong in vitro inhibitory phenotype, loss of GOT2 had 
      no effect on tumor growth in xenograft PDA or autochthonous mouse models. We show 
      that cancer-associated fibroblasts (CAFs), a major component of the pancreatic 
      tumor microenvironment (TME), release the redox active metabolite pyruvate, and 
      culturing GOT2 KD cells in CAF conditioned media (CM) rescued proliferation in 
      vitro. Furthermore, blocking pyruvate import or pyruvate-to-lactate reduction 
      prevented rescue of GOT2 KD in vitro by exogenous pyruvate or CAF CM. However, 
      these interventions failed to sensitize xenografts to GOT2 KD in vivo, 
      demonstrating the remarkable plasticity and differential metabolism deployed by 
      PDA cells in vitro and in vivo. This emphasizes how the environmental context of 
      distinct pre-clinical models impacts both cell-intrinsic metabolic rewiring and 
      metabolic crosstalk with the TME.
CI  - (c) 2022, Kerk et al.
FAU - Kerk, Samuel A
AU  - Kerk SA
AUID- ORCID: 0000-0001-9786-2245
AD  - Doctoral Program in Cancer Biology, University of Michigan-Ann Arbor, Ann Arbor, 
      United States.
FAU - Lin, Lin
AU  - Lin L
AD  - Department of Molecular and Integrative Physiology, University of Michigan-Ann 
      Arbor, Ann Arbor, United States.
FAU - Myers, Amy L
AU  - Myers AL
AD  - Department of Molecular and Integrative Physiology, University of Michigan-Ann 
      Arbor, Ann Arbor, United States.
FAU - Sutton, Damien J
AU  - Sutton DJ
AD  - Department of Molecular and Integrative Physiology, University of Michigan-Ann 
      Arbor, Ann Arbor, United States.
FAU - Andren, Anthony
AU  - Andren A
AD  - Department of Molecular and Integrative Physiology, University of Michigan-Ann 
      Arbor, Ann Arbor, United States.
FAU - Sajjakulnukit, Peter
AU  - Sajjakulnukit P
AD  - Doctoral Program in Cancer Biology, University of Michigan-Ann Arbor, Ann Arbor, 
      United States.
FAU - Zhang, Li
AU  - Zhang L
AD  - Department of Molecular and Integrative Physiology, University of Michigan-Ann 
      Arbor, Ann Arbor, United States.
FAU - Zhang, Yaqing
AU  - Zhang Y
AD  - Department of Surgery, University of Michigan-Ann Arbor, Ann Arbor, United 
      States.
FAU - Jimenez, Jennifer A
AU  - Jimenez JA
AD  - Doctoral Program in Cancer Biology, University of Michigan-Ann Arbor, Ann Arbor, 
      United States.
FAU - Nelson, Barbara S
AU  - Nelson BS
AD  - Doctoral Program in Cancer Biology, University of Michigan-Ann Arbor, Ann Arbor, 
      United States.
AD  - Department of Molecular and Integrative Physiology, University of Michigan-Ann 
      Arbor, Ann Arbor, United States.
FAU - Chen, Brandon
AU  - Chen B
AD  - Department of Molecular and Integrative Physiology, University of Michigan-Ann 
      Arbor, Ann Arbor, United States.
FAU - Robinson, Anthony
AU  - Robinson A
AD  - Department of Cell and Developmental Biology, University of Michigan-Ann Arbor, 
      Ann Arbor, United States.
FAU - Thurston, Galloway
AU  - Thurston G
AD  - Department of Molecular and Integrative Physiology, University of Michigan-Ann 
      Arbor, Ann Arbor, United States.
FAU - Kemp, Samantha B
AU  - Kemp SB
AD  - Molecular and Cellular Pathology Graduate Program, University of Michigan-Ann 
      Arbor, Ann Arbor, United States.
FAU - Steele, Nina G
AU  - Steele NG
AD  - Department of Cell and Developmental Biology, University of Michigan-Ann Arbor, 
      Ann Arbor, United States.
FAU - Hoffman, Megan T
AU  - Hoffman MT
AD  - Department of Molecular and Integrative Physiology, University of Michigan-Ann 
      Arbor, Ann Arbor, United States.
FAU - Wen, Hui-Ju
AU  - Wen HJ
AD  - Department of Molecular and Integrative Physiology, University of Michigan-Ann 
      Arbor, Ann Arbor, United States.
FAU - Long, Daniel
AU  - Long D
AD  - Department of Molecular and Integrative Physiology, University of Michigan-Ann 
      Arbor, Ann Arbor, United States.
FAU - Ackenhusen, Sarah E
AU  - Ackenhusen SE
AD  - Program in Chemical Biology, University of Michigan-Ann Arbor, Ann Arbor, United 
      States.
FAU - Ramos, Johanna
AU  - Ramos J
AD  - Department of Molecular and Integrative Physiology, University of Michigan-Ann 
      Arbor, Ann Arbor, United States.
FAU - Gao, Xiaohua
AU  - Gao X
AD  - Department of Molecular and Integrative Physiology, University of Michigan-Ann 
      Arbor, Ann Arbor, United States.
FAU - Nwosu, Zeribe C
AU  - Nwosu ZC
AD  - Department of Molecular and Integrative Physiology, University of Michigan-Ann 
      Arbor, Ann Arbor, United States.
FAU - Galban, Stefanie
AU  - Galban S
AD  - Department of Radiology, University of Michigan, Ann Arbor, United States.
AD  - Rogel Cancer Center, University of Michigan, Ann Arbor, United States.
FAU - Halbrook, Christopher J
AU  - Halbrook CJ
AD  - Department of Molecular and Integrative Physiology, University of Michigan-Ann 
      Arbor, Ann Arbor, United States.
FAU - Lombard, David B
AU  - Lombard DB
AD  - Department of Pathology and Institute of Gerontology, University of Michigan, Ann 
      Arbor, United States.
FAU - Piwnica-Worms, David R
AU  - Piwnica-Worms DR
AD  - Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer 
      Center, Houston, United States.
FAU - Ying, Haoqiang
AU  - Ying H
AD  - Department of Molecular and Cellular Oncology, University of Texas MD Anderson 
      Cancer Center, Houston, United States.
FAU - Pasca di Magliano, Marina
AU  - Pasca di Magliano M
AUID- ORCID: 0000-0001-9632-9035
AD  - Department of Surgery, University of Michigan-Ann Arbor, Ann Arbor, United 
      States.
AD  - Rogel Cancer Center, University of Michigan, Ann Arbor, United States.
FAU - Crawford, Howard C
AU  - Crawford HC
AD  - Department of Molecular and Integrative Physiology, University of Michigan-Ann 
      Arbor, Ann Arbor, United States.
AD  - Rogel Cancer Center, University of Michigan, Ann Arbor, United States.
FAU - Shah, Yatrik M
AU  - Shah YM
AD  - Department of Molecular and Integrative Physiology, University of Michigan-Ann 
      Arbor, Ann Arbor, United States.
AD  - Rogel Cancer Center, University of Michigan, Ann Arbor, United States.
AD  - Department of Internal Medicine, Division of Gastroenterology and Hepatology, 
      University of Michigan, Ann Arbor, United States.
FAU - Lyssiotis, Costas A
AU  - Lyssiotis CA
AUID- ORCID: 0000-0001-9309-6141
AD  - Doctoral Program in Cancer Biology, University of Michigan-Ann Arbor, Ann Arbor, 
      United States.
AD  - Department of Molecular and Integrative Physiology, University of Michigan-Ann 
      Arbor, Ann Arbor, United States.
AD  - Rogel Cancer Center, University of Michigan, Ann Arbor, United States.
AD  - Department of Internal Medicine, Division of Gastroenterology and Hepatology, 
      University of Michigan, Ann Arbor, United States.
LA  - eng
GR  - P30 DK034933/DK/NIDDK NIH HHS/United States
GR  - K99 CA241357/CA/NCI NIH HHS/United States
GR  - R01 CA248160/CA/NCI NIH HHS/United States
GR  - R01 GM101171/GM/NIGMS NIH HHS/United States
GR  - T32 CA009676/CA/NCI NIH HHS/United States
GR  - P30 CA046592/CA/NCI NIH HHS/United States
GR  - T32 DK094775/DK/NIDDK NIH HHS/United States
GR  - F31 CA254079/CA/NCI NIH HHS/United States
GR  - F31 CA247457/CA/NCI NIH HHS/United States
GR  - R01 CA253986/CA/NCI NIH HHS/United States
GR  - F31 CA247076/CA/NCI NIH HHS/United States
GR  - F99 CA264414/CA/NCI NIH HHS/United States
GR  - R01 CA244931/CA/NCI NIH HHS/United States
GR  - R50 CA232985/CA/NCI NIH HHS/United States
GR  - R37 CA237421/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20220711
PL  - England
TA  - Elife
JT  - eLife
JID - 101579614
RN  - 0 (Fatty Acid-Binding Proteins)
RN  - 0U46U6E8UK (NAD)
RN  - 8558G7RUTR (Pyruvic Acid)
RN  - EC 2.6.1.- (Aspartate Aminotransferase, Mitochondrial)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
SB  - IM
CIN - Trends Cancer. 2022 Nov;8(11):884-886. PMID: 36153305
MH  - Animals
MH  - Aspartate Aminotransferase, Mitochondrial/genetics/metabolism
MH  - *Carcinoma, Pancreatic Ductal/pathology
MH  - Fatty Acid-Binding Proteins
MH  - Humans
MH  - Mice
MH  - NAD/metabolism
MH  - *Pancreatic Neoplasms/pathology
MH  - Proto-Oncogene Proteins p21(ras)/metabolism
MH  - Pyruvic Acid/metabolism
MH  - Tumor Microenvironment
PMC - PMC9328765
OTO - NOTNLM
OT  - biochemistry
OT  - cancer biology
OT  - chemical biology
OT  - human
OT  - mouse
OT  - pancreatic cancer
OT  - tumor metabolism
OT  - tumor microenvironment
COIS- SK, LL, AM, DS, AA, PS, LZ, YZ, JJ, BN, BC, AR, GT, SK, NS, MH, HW, DL, SA, JR, 
      XG, ZN, SG, CH, DL, DP, HY, MP, HC, YS, CL No competing interests declared
EDAT- 2022/07/12 06:00
MHDA- 2022/07/29 06:00
PMCR- 2022/07/11
CRDT- 2022/07/11 08:53
PHST- 2021/08/21 00:00 [received]
PHST- 2022/07/09 00:00 [accepted]
PHST- 2022/07/12 06:00 [pubmed]
PHST- 2022/07/29 06:00 [medline]
PHST- 2022/07/11 08:53 [entrez]
PHST- 2022/07/11 00:00 [pmc-release]
AID - 73245 [pii]
AID - 10.7554/eLife.73245 [doi]
PST - epublish
SO  - Elife. 2022 Jul 11;11:e73245. doi: 10.7554/eLife.73245.