A Review of Metabolic Stress and Development of Pancreatic Cancer

LI Jin-tao, LEI Ming-zhu, LEI Qun-ying, YIN Miao


Pancreatic ductal adenocarcinoma (PDAC) is one of the most notorious malignancies with a 5-year survival rate of less than 8%. Therefore, it is crucial to investigate the molecular mechanism underlining PDAC initiation, promotion, and progression for efficient treatment of PDAC. In order to adapt and survive in an extremely adverse microenvironment of hypoxia and insufficiency of nutrients and energy, PDAC cells undergo extensive metabolic modification triggered by intrinsic signalings which are activated by different genetic events, including mutations occurred at KRAS, TP53, and DPC4/SMAD4, collaboratively promoting PDAC development. Notably, PDCA cells have extensive crosstalk in the form of reciprocal metabolic flux with its surrounding microenvironment to facilitate tumor advancement and therapy resistance. We herein summarize recent findings of PDAC metabolism and discuss metabolic rewiring-based therapeutic strategies.


Keywords: Pancreatic ductal adenocarcinoma, Metabolism, Tumor microenvironment


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RHIM A D, MIREK E T, AIELLO N M, et al. EMT and dissemination precede pancreatic tumor formation. Cell,2012,148(1/2): 349–361.

LI J T, WANG Y P, YIN M, et al. Metabolism remodeling in pancreatic ductal adenocarcinoma. Cell Stress,2019,3(12): 361–368.

HAN H, VON HOFF D D. SnapShot: pancreatic cancer. Cancer Cell, 2013,23(3): 424e1[2020-12-25]. https://doi.org/10.1016/j.ccr.2013.03.008.

ROOMAN I, REAL F X. Pancreatic ductal adenocarcinoma and acinar WARBURG O. Origin of cancer cells. Oncologia,1956,9(2): 75–83.

BRYANT K L, MANCIAS J D, KIMMELMAN A C, et al. KRAS: feeding pancreatic cancer proliferation. Trends Biochem Sci,2014,39(2): 91–100.

GAGLIO D, METALLO C M, GAMEIRO P A, et al. Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth. Mol Syst Biol,2011,7: 523[2020-12-25]. https://doi.org/10. 1038/msb.2011.56.

YING H, KIMMELMAN A C, LYSSIOTIS C A, et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell,2012,149(3): 656–670.

MA Z, VOCADLO D J, VOSSELLER K. Hyper-O-GlcNAcylation is anti-apoptotic and maintains constitutive NF-kappaB activity in pancreatic cancer cells. J Biol Chem,2013,288(21): 15121–15130.

BOTT A J, SHEN J, TONELLI C, et al. Glutamine anabolism plays a critical role in pancreatic cancer by coupling carbon and nitrogen metabolism. Cell Rep,2019,29(5): 1287–1298.

YANG S, HWANG S, KIM M, et al. Mitochondrial glutamine metabolism via GOT2 supports pancreatic cancer growth through senescence inhibition. Cell Death Dis,2018,9(2): 55[2020-12-25]. https://doi.org/10.1038/s41419-017-0089-1.

SON J, LYSSIOTIS C A, YING H, et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature, 2013,496(7443): 101–105.

KONG B, QIA C, ERKAN M, et al. Overview on how oncogenic Kras promotes pancreatic carcinogenesis by inducing low intracellular ROS levels. Front Physiol,2013(4): 246[2020-12-25]. https://doi.org/10. 3389/fphys.2013.00246.

CHIO I I C, JAFARNEJAD S M, PONZ-SARVISE M, et al. NRF2 promotes tumor maintenance by modulating mRNA translation in pancreatic cancer. Cell,2016,166(4): 963–976.

O'BRYAN J P. Pharmacological targeting of RAS: recent success with direct inhibitors. Pharmacol Res,2019,139: 503–511.

KIM D, XUE J Y, LITO P. Targeting KRAS(G12C): from inhibitory mechanism to modulation of antitumor effects in patients. Cell,2020, 183(4): 850–859.

SCHOFIELD H K, ZELLER J, ESPINOZA C, et al. Mutant p53R270H drives altered metabolism and increased invasion in pancreatic ductal adenocarcinoma. JCI Insight,2018,3(2): e97422[2020-12-25]. https://doi.org/10.1172/jci.insight.97422.

MORRIS J P T, YASHINSKIE J J, KOCHE R, et al. Alpha-ketoglutarate links p53 to cell fate during tumour suppression. Nature,2019,573(7775): 595–599.

BUTERA G, PACCHIANA R, MULLAPPILLY N, et al. Mutant p53 prevents GAPDH nuclear translocation in pancreatic cancer cells favoring glycolysis and 2-deoxyglucose sensitivity. Biochim Biophys Acta Mol Cell Res,2018,1865(12): 1914–1923.

CARRER A, TREFELY S, ZHAO S, et al. Acetyl-CoA metabolism supports multistep pancreatic tumorigenesis. Cancer Discov,2019,9(3): 416–435.

LEE J H, CHO Y R, KIM J H, et al. Branched-chain amino acids sustain pancreatic cancer growth by regulating lipid metabolism. Exp Mol Med, 2019,51(11): 1–11.

LI J T, YIN M, WANG D, et al. BCAT2-mediated BCAA catabolism is critical for development of pancreatic ductal adenocarcinoma. Nat Cell Biol,2020,22(2): 167–174.

LEI M Z, LI X X, ZHANG Y, et al. Acetylation promotes BCAT2 degradation to suppress BCAA catabolism and pancreatic cancer growth. Signal Transduct Target Ther ,2020,5(1): 70[2020-12-25]. https://doi.org/10.1038/s41392-020-0168-0.

BADGLEY M A, KREMER D M, MAURER H C, et al. Cysteine depletion induces pancreatic tumor ferroptosis in mice. Science,2020, 368(6486): 85–89.

DAHER B, PARKS S K, DURIVAULT J, et al. Genetic ablation of the cystine transporter xCT in PDAC cells inhibits mTORC1, growth, survival, and tumor formation via nutrient and oxidative stresses. Cancer Res,2019,79(15): 3877–3890.

ZAYTOUNI T, TSAI P Y, HITCHCOCK D S, et al. Critical role for arginase 2 in obesity-associated pancreatic cancer. Nat Commun,2017, 8(1): 242[2020-12-25]. https://doi.org/10.1038/s41467-017-00331-y.

HUI S, GHERGUROVICH J M, MORSCHER R J, et al. Glucose feeds the TCA cycle via circulating lactate. Nature,2017,551(7678): 115–118.

JIANG S H, LI J, DONG F Y, et al. Increased serotonin signaling contributes to the Warburg effect in pancreatic tumor cells under metabolic stress and promotes growth of pancreatic tumors in mice. Gastroenterology,2017,153(1): 277–911.

BAENKE F, PECK B, MIESS H, et al. Hooked on fat: the role of lipid synthesis in cancer metabolism and tumour development. Dis Model Mech,2013,6(6): 1353–1363.

SWIERCZYNSKI J, HEBANOWSKA A, SLEDZINSKI T. Role of abnormal lipid metabolism in development, progression, diagnosis and therapy of pancreatic cancer. World J Gastroenterol,2014,20(9): 2279–2303.

HATZIVASSILIOU G, ZHAO F, BAUER D E, et al. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell,2005,8(4): 311–321.

TADROS S, SHUKLA S K, KING R J, et al. De Novo lipid synthesis facilitates gemcitabine resistance through endoplasmic reticulum stress in pancreatic cancer. Cancer Res,2017,77(20): 5503–5517.


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