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@ARTICLE{Jian:137682,
      author       = {Z. Jian and T. Cheng and Z. Zhang and S. Raulefs and K. Shi
                      and K. Steiger and N. Maeritz and K. Kleigrewe and T.
                      Hofmann and S. Benitz and P. E. Bruns$^*$ and D. Lamp and M.
                      Jastroch and J. Akkan and C. Jäger and P. Huang and S. Nie
                      and S. Shen and X. Zou and G. O. Ceyhan and C. W. Michalski
                      and H. Friess and J. Kleeff and B. Kong$^*$},
      title        = {{G}lycemic {V}ariability {P}romotes {B}oth {L}ocal
                      {I}nvasion and {M}etastatic {C}olonization by {P}ancreatic
                      {D}uctal {A}denocarcinoma.},
      journal      = {Cellular and Molecular Gastroenterology and Hepatology},
      volume       = {6},
      number       = {4},
      issn         = {2352-345X},
      address      = {New York, NY},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2018-01559},
      pages        = {429 - 449},
      year         = {2018},
      abstract     = {Although nearly half of pancreatic ductal adenocarcinoma
                      (PDAC) patients have diabetes mellitus with episodes of
                      hyperglycemia, its tumor microenvironment is hypoglycemic.
                      Thus, it is crucial for PDAC cells to develop adaptive
                      mechanisms dealing with oscillating glucose levels. So far,
                      the biological impact of such glycemic variability on PDAC
                      biology remains unknown.Murine PDAC cells were cultured in
                      low- and high-glucose medium to investigate the molecular,
                      biochemical, and metabolic influence of glycemic variability
                      on tumor behavior. A set of in vivo functional assays
                      including orthotopic implantation and portal and tail vein
                      injection were used. Results were further confirmed on
                      tissues from PDAC patients.Glycemic variability has no
                      significant effect on PDAC cell proliferation. Hypoglycemia
                      is associated with local invasion and angiogenesis, whereas
                      hyperglycemia promotes metastatic colonization. Increased
                      metastatic colonization under hyperglycemia is due to
                      increased expression of runt related transcription factor 3
                      (Runx3), which further activates expression of collagen,
                      type VI, alpha 1 (Col6a1), forming a glycemic pro-metastatic
                      pathway. Through epigenetic machinery, retinoic acid
                      receptor beta (Rarb) expression fluctuates according to
                      glycemic variability, acting as a critical sensor relaying
                      the glycemic signal to Runx3/Col6a1. Moreover, the signal
                      axis of Rarb/Runx3/Col6a1 is pharmaceutically accessible to
                      a widely used antidiabetic substance, metformin, and Rar
                      modulator. Finally, PDAC tissues from patients with diabetes
                      show an increased expression of COL6A1.Glycemic variability
                      promotes both local invasion and metastatic colonization of
                      PDAC. A pro-metastatic signal axis Rarb/Runx3/Col6a1 whose
                      activity is controlled by glycemic variability is
                      identified. The therapeutic relevance of this pathway needs
                      to be explored in PDAC patients, especially in those with
                      diabetes.},
      cin          = {G200},
      ddc          = {610},
      cid          = {I:(DE-He78)G200-20160331},
      pnm          = {317 - Translational cancer research (POF3-317)},
      pid          = {G:(DE-HGF)POF3-317},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:30258965},
      pmc          = {pmc:PMC6154439},
      doi          = {10.1016/j.jcmgh.2018.07.003},
      url          = {https://inrepo02.dkfz.de/record/137682},
}