PLoS ONE (Jan 2017)

Dusp3 deletion in mice promotes experimental lung tumour metastasis in a macrophage dependent manner.

  • Maud Vandereyken,
  • Sophie Jacques,
  • Eva Van Overmeire,
  • Mathieu Amand,
  • Natacha Rocks,
  • Céline Delierneux,
  • Pratibha Singh,
  • Maneesh Singh,
  • Camille Ghuysen,
  • Caroline Wathieu,
  • Tinatin Zurashvili,
  • Nor Eddine Sounni,
  • Michel Moutschen,
  • Christine Gilles,
  • Cécile Oury,
  • Didier Cataldo,
  • Jo A Van Ginderachter,
  • Souad Rahmouni

DOI
https://doi.org/10.1371/journal.pone.0185786
Journal volume & issue
Vol. 12, no. 10
p. e0185786

Abstract

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Vaccinia-H1 Related (VHR) dual-specificity phosphatase, or DUSP3, plays an important role in cell cycle regulation and its expression is altered in several human cancers. In mouse model, DUSP3 deletion prevents neo-angiogenesis and b-FGF-induced microvessel outgrowth. Considering the importance of angiogenesis in metastasis formation, our study aimed to investigate the role of DUSP3 in tumour cell dissemination. Using a Lewis Lung carcinoma (LLC) experimental metastasis model, we observed that DUSP3-/- mice developed larger lung metastases than littermate controls. DUSP3-/- bone marrow transfer to lethally irradiated DUSP3+/+ mice was sufficient to transfer the phenotype to DUSP3+/+ mice, indicating that hematopoietic cells compartment was involved in the increased tumour cell dissemination to lung tissues. Interestingly, we found a higher percentage of tumour-promoting Ly6Cint macrophages in DUSP3-/- LLC-bearing lung homogenates that was at least partially due to a better recruitment of these cells. This was confirmed by 1) the presence of higher number of the Ly6Bhi macrophages in DUSP3-/- lung homogenates and by 2) the better migration of DUSP3-/- bone marrow sorted monocytes, peritoneal macrophages and bone marrow derived macrophages (BMDMs), compared to DUSP3+/+ monocytes, macrophages and BMDMs, in response to LLC-conditioned medium. Our study demonstrates that DUSP3 phosphatase plays a key role in metastatic growth through a mechanism involving the recruitment of macrophages towards LLC-bearing lungs.