Host JDP2 expression in the bone marrow contributes to metastatic spread.

Yelena Barbarov,Tsonwin Hai,Dror Alishekevitz,Kazunari K. Yokoyama,Michael Timaner,Ami Aronheim,Yuval Shaked

doi:10.18632/oncotarget.5648

Abstract

The c-Jun Dimerization Protein 2, JDP2, is a basic leucine zipper protein member of the activator protein-1 (AP-1) family of transcription factors. JDP2 typically suppresses gene transcription through multiple mechanisms and plays a dual role in multiple cellular processes, including cell differentiation and proliferation which is dependent on AP-1 function. Whereas the role of JDP2 expression within cancer cells has been studied, its role in stromal cells at the tumor microenvironment is largely unknown. Here we show that mice lacking JDP2 (JDP2-/-) display a reduced rate of metastasis in Lewis lung carcinoma (LLC) and polyoma middle T-antigen (PyMT) breast carcinoma mouse models. The replacement of wild-type bone marrow derived cells (BMDCs) with JDP2-deficient BMDCs recapitulates the metastatic phenotype of JDP2-/- tumor-bearing mice. In vitro, conditioned medium of wild-type BMDCs significantly potentiates the migration and invasion capacity of LLC cells as compared to that of JDP2-/- BMDCs. Furthermore, wild-type BMDCs secrete CCL5, a chemokine known to contribute to metastasis, to a greater extent than JDP2-/- BMDCs. The supplementation of CCL5 in JDP2-/- BMDC conditioned medium was sufficient to potentiate the invasion capacity of LLC. Overall, this study suggests that JDP2-expressing BMDCs within the tumor microenvironment contribute to metastatic spread.

Highlights

Tumor growth is dependent on both the proliferation of cancer cells as well as the infiltration of different host cells which together with resident stromal cells constitute the tumor microenvironment
In which Lewis lung carcinoma (LLC) cells were subcutaneously implanted into the flanks of wild-type and JDP2−/− mice, tumors from wild-type mice were found to be relatively smaller than tumors from JDP2 −/− mice, these differences were not statistically significant (Figure 2A)
Using mice harboring a homozygous mutation in the JDP2 allele, we characterized the role of JDP2 expression in noncancer cells on cancer development and metastasis

Summary

Introduction

Tumor growth is dependent on both the proliferation of cancer cells as well as the infiltration of different host cells which together with resident stromal cells constitute the tumor microenvironment. The interaction between cancer and stromal cells creates a permissive environment which promotes tumor growth and metastasis [1, 2]. Tumor associated neutrophils (TANs) synthesize various cytokines and chemokines as well as pro-angiogenic factors [3]. Both macrophages and neutrophils are sources of toxic substances capable of www.impactjournals.com/oncotarget killing invading pathogens and cancer cells. The delicate balance between the different stromal cells within the tumor microenvironment has a dramatic impact on tumor growth and metastasis. We focused on the expression of the c-Jun dimerization protein, 2 (JDP2) transcription repressor in the host and studied the effect of JDP2 ablation on tumor and metastatic growth

Methods

Results

Conclusion