ATF3 and JDP2 deficiency in cancer associated fibroblasts promotes tumor growth via SDF-1 transcription

Oncogene. 2019 May;38(20):3812-3823. doi: 10.1038/s41388-019-0692-y. Epub 2019 Jan 22.


The activating transcription factor 3 (ATF3) and the c-Jun dimerization protein 2 (JDP2) are members of the basic leucine zipper (bZIP) family of transcription factors. These proteins share a high degree of homology and both can activate or repress transcription. Deficiency of either one of them in the non-cancer host cells was shown to reduce metastases. As ATF3 and JDP2 compensate each other's function, we studied the double deficiency of ATF3 and JDP2 in the stromal tumor microenvironment. Here, we show that mice with ATF3 and JDP2 double deficiency (designated thereafter dKO) developed larger tumors with high vascular perfusion and increased cell proliferation rate compared to wild type (WT) mice. We further identify that the underlying mechanism involves tumor associated fibroblasts which secrete high levels of stromal cell-derived factor 1 (SDF-1) in dKO fibroblasts. SDF-1 depletion in dKO fibroblasts dampened tumor growth and blood vessel perfusion. Furthermore, ATF3 and JDP2 were found to regulate SDF-1 transcription and secretion in fibroblasts, a phenomenon that is potentiated in the presence of cancer cells. Collectively, our results suggest that ATF3 and JDP2 regulate the expression of essential tumor promoting factors expressed by fibroblasts within the tumor microenvironment, and thus restrain tumor growth.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 3 / genetics
  • Activating Transcription Factor 3 / metabolism*
  • Animals
  • Blood Vessels / pathology
  • Bone Marrow Transplantation
  • Cancer-Associated Fibroblasts / metabolism
  • Cancer-Associated Fibroblasts / pathology*
  • Cell Proliferation / genetics
  • Chemokine CXCL12 / genetics
  • Chemokine CXCL12 / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Humans
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / pathology
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Tumor Microenvironment / genetics
  • Xenograft Model Antitumor Assays


  • Activating Transcription Factor 3
  • Atf3 protein, mouse
  • Chemokine CXCL12
  • Cxcl12 protein, mouse
  • JDP2 protein, human
  • Repressor Proteins