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Abstract
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.
Highlights
DUSP3, or Vaccinia H1-Related (VHR), is a member of the atypical dual-specificity protein phosphatase family (A-DUSPs)
In this study, using a Lewis Lung carcinoma (LLC)-experimental metastasis model and DUSP3-deficient mice, we reported that the phosphatase DUSP3 is a key player in metastatic growth, modulating the recruitment of macrophages towards LLC-bearing lungs
We showed that matrigel plugs and LLC subcutaneous tumours were less vascularized in DUSP3-/- mice compared to DUSP3+/+ littermates
Summary
Purified anti-CD16/CD32 (FcγIII/II receptor) (2.4G2), PE-anti-Ly6G (1A8), APC-Cy7 antiLy6G (1A8), V450-anti-CD45.2 (A20), V500-anti-I-A/I-E (MHC-II) (M5/114.15.2), APCanti-CD11c (HL3), APC-Cy7 anti-CD11c (HL3), PE anti-Siglec-F (E50-2440), PE-Cy7-streptavidin and Biotin anti-IgG2B (RG/11.1) were from BD Biosciences (BD Biosciences, San Jose, CA). APC-anti-F4/80 (BM8) and PerCp-Cy5-anti-CD11b (M1/70) were from eBiosciences (eBioscience, San Diego, CA). Alexa 647-anti-CD206 (C068C2) and PE-Cy7-anti F4/80 (BM8) were from Biolegend (Biolegend, San Diego, CA). Alexa647 anti-Ly6b.2 (7/4) and Alexa 488-anti-Ly6G (ER-MP20) were from AbD Serotec (AbD Serotec, Kidlington, UK). AntiVHR (DUSP3) (sc8889) antibody was from Santa Cruz (Santa Cruz, Dallas, Texas). AntiGAPDH antibody was from Sigma (Sigma-Aldrich, Diegem, Belgium). Anti-Ki67 antibody was from Abcam (Abcam, Cambridge, UK). HRP-conjugated anti-goat, anti-mouse and antirabbit were used as secondary antibodies and were from Amersham Biosciences (Amersham Biosciences, GlattBrugg, Switzerland). Collagenase I and DNaseI were from Roche (Roche, Basel, Switzerland)
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