Adipocytes WNT5a mediated dedifferentiation: a possible target in pancreatic cancer microenvironment

Oncotarget. 2016 Apr 12;7(15):20223-35. doi: 10.18632/oncotarget.7936.


A significant epidemiological association between obesity and pancreatic ductal adenocarcinoma (PDAC) has previously been described, as well as a correlation between the degree of pancreatic steatosis, PDAC risk and prognosis. The underlying mechanisms are still not completely known.After co-culture of 3T3-L1 adipocytes and MiaPaCa2 with an in vitro transwell system we observed the appearance of fibroblast-like cells, along with a decrease in number and size of remaining adipocytes. RT-PCR analyses of 3T3-L1 adipocytes in co-culture showed a decrease in gene expression of typical markers of mature adipocytes, in parallel with an increased expression of fibroblast-specific and reprogramming genes. We found an increased WNT5a gene and protein expression early in MiaPaCa2 cells in co-culture. Additionally, EMSA of c-Jun and AP1 in 3T3-L1 demonstrated an increased activation in adipocytes after co-culture. Treatment with WNT5a neutralizing antibody completely reverted the activation of c-Jun and AP1 observed in co-cultured adipocytes.Increasing doses of recombinant SFRP-5, a competitive inhibitor for WNT5a receptor, added to the co-culture medium, were able to block the dedifferentiation of adipocytes in co-culture.These data support a WNT5a-mediated dedifferentiation process with adipocytes reprogramming toward fibroblast-like cells that might profoundly influence cancer microenvironment.

Keywords: WNT5a; adipocytes; cell dedifferentiation; pancreatic cancer; tumor microenvironment.

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / metabolism
  • Adipocytes / pathology*
  • Animals
  • Apoptosis
  • Cell Dedifferentiation*
  • Cell Proliferation
  • Cells, Cultured
  • Coculture Techniques
  • Fibroblasts / metabolism
  • Fibroblasts / pathology*
  • Mice
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • Tumor Microenvironment
  • Wnt-5a Protein / metabolism*


  • Wnt-5a Protein