Basic—Liver, Pancreas, and Biliary TractE-Cadherin Regulates Metastasis of Pancreatic Cancer In Vivo and Is Suppressed by a SNAIL/HDAC1/HDAC2 Repressor Complex
Section snippets
Generation of Primary Murine PDAC Cell Lines
Tumors from Ptf1a/p48ex1Cre/+;LSL-KRASG12D/+ or Ptf1a/p48ex1Cre/+;LSL-KRASG12D/+;TP53lox/lox mice were removed and digested in 10 mL Dulbecco's modified Eagle medium (DMEM) containing 150 U/mL collagenase Type 2 (Worthington, Lakewood, NJ) as described.20 Digested tumors were dispersed into single cell suspension, resuspended in DMEM medium containing 10% fetal calf serum (FCS), and cultivated as described.21, 22
Chromatin Immunoprecipitation Assay
Chromatin immunoprecipitation (ChIP) assays were performed as recently described23
In Vivo Selection for Lung Metastasis of Pancreatic Cancer Cells
To detect pathways involved in metastasis of PDAC, we used an established in vivo selection model19 as shown in Supplementary Figure S1A. Murine TD-2EGFP-fLuc-TVA pancreatic cancer cells that exhibited high tumorigenicity at the site of injection while having low metastatic potential to the lung21 were injected into the tail vein of nude mice, and the metastatic process was longitudinally monitored by in vivo bioluminescence imaging (Supplementary Figure 1B). At necropsy, metastases were
Discussion
In this study, we demonstrate the importance of E-cadherin silencing for EMT and the metastatic process of PDAC in vitro and in vivo using different murine and human pancreatic cancer models. Conceivably, E-cadherin could be silenced during tumor progression and metastasis by somatic mutations, promoter methylation, or transcriptional repression. However, a recent study detected no CDH1 gene mutations in human PDAC.18 Although hypermethylation of the CDH1 promoter was observed in the pancreatic
Acknowledgments
J.v.B. and S.E. contributed equally to this work.
The authors thank Dr Bates, Dr Li, and Dr Hughes for providing plasmids; Dr Jacks and Dr Tuveson for LSL-KRASG12D mice, Dr Berns for TP53lox/lox mice, and Dr Nakhai for Ptf1a/p48ex1Cre/+ mice; Dr Greten for TD-2 cells; U. Götz, M. Werb, and M. Göbel for excellent technical assistance; and the Microarray Core Unit headed by Dr R. Lang for Affymetrix GeneChip analysis.
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Conflicts of interest The authors disclose no conflicts.
Funding Supported by Deutsche Krebshilfe (project 107143, to D.S.) and Deutsche Forschungsgemeinschaft (SCHN 959/1-1) and SFB456 (to G.S.).