, Chemokine (C-C motif) receptor 4; CCL17, Chemokine (C-C motif, CCR4, p.17

C. Ccl22 and . Motif, MDC, p.22

, CLDN1, p.1

, Tregs, regulatory T cells

, AKT, v-akt murine thymoma viral oncogene homolog 1

I. Ic,

F. Fitc and . Isothiocyanate,

A. ;. Ab and . Ha, Human Astrocytes; hCMEC/D3, Immortalized human brain endothelial cells; RT-qPCR, Quantitative real-time PCR

I. ;. Ip and ;. Braf, murine sarcoma viral oncogene homolog B1; CCR4 hi , CCR4 over expressing melanoma cells/CCR4 high; SFM, Serum Free Media; CM, Conditioned medium; DMSO

, Extracellular Matrix; FCS, Fetal calf serum, ECM

, Human brain-metastasizing melanoma cells, HBMMC

I. P. Witz, Tumor-microenvironment interactions: dangerous liaisons, Adv Cancer Res, vol.100, pp.203-232, 2008.

A. Klein-goldberg, S. Maman, and I. P. Witz, The role played by the microenvironment in site-specific metastasis, Cancer Lett, vol.352, pp.54-62, 2014.

S. Maman and I. P. Witz, The Metastatic Microenvironment, pp.15-38, 2013.

I. Nevo, O. Sagi-assif, L. E. Botzer, D. Amar, S. Maman et al., Generation and characterization of novel local and metastatic human neuroblastoma variants, Neoplasia, vol.10, pp.817-67, 2008.

S. Izraely, O. Sagi-assif, A. Klein, T. Meshel, G. Tsarfaty et al., The metastatic microenvironment: brainresiding melanoma metastasis and dormant micrometastasis, Int J Cancer, vol.131, pp.1071-82, 2012.

S. Izraely, A. Klein, O. Sagi-assif, T. Meshel, G. Tsarfaty et al., Chemokine-chemokine receptor axes in melanoma brain metastasis, Immunol Lett, vol.130, pp.107-121, 2010.

S. Izraely, O. Sagi-assif, A. Klein, T. Meshel, S. Ben-menachem et al., The metastatic microenvironment: Claudin-1 suppresses the malignant phenotype of melanoma brain metastasis, Int J Cancer, vol.136, pp.1296-307, 2015.

C. H. Kim and H. E. Broxmeyer, Chemokines: signal lamps for trafficking of T and B cells for development and effector function, J Leukoc Biol, vol.65, pp.6-15, 1999.

O. Yoshie and K. Matsushima, CCR4 and its ligands: from bench to bedside, Int Immunol, vol.27, pp.11-20, 2015.

T. Ishida and R. Ueda, CCR4 as a novel molecular target for immunotherapy of cancer, Cancer Science, vol.97, pp.1139-1146, 2006.

J. H. Lee, Y. S. Cho, J. Y. Lee, M. C. Kook, J. W. Park et al., The chemokine receptor CCR4 is expressed and associated with a poor prognosis in patients with gastric cancer, Ann Surg, vol.249, pp.933-974, 2009.

A. Klein, O. Sagi-assif, S. Izraely, T. Meshel, M. Pasmanik-chor et al., The metastatic microenvironment: Brain-derived soluble factors alter the malignant phenotype of cutaneous and brain-metastasizing melanoma cells, Int J Cancer, vol.131, pp.2509-2527, 2012.

I. Zubrilov, O. Sagi-assif, S. Izraely, T. Meshel, S. Ben-menahem et al., Vemurafenib resistance selects for highly malignant brain and lung-metastasizing melanoma cells, Cancer Lett, vol.361, pp.86-96, 2015.
URL : https://hal.archives-ouvertes.fr/hal-02411572

B. M. Baker and C. S. Chen, Deconstructing the third dimension: how 3D culture microenvironments alter cellular cues, J Cell Sci, vol.125, pp.3015-3039, 2012.

M. Miron-mendoza, V. Koppaka, C. Zhou, and W. M. Petroll, Techniques for assessing 3-D cell-matrix mechanical interactions in vitro and in vivo, Exp Cell Res, vol.319, pp.2470-80, 2013.

S. Zhang, Designer self-assembling Peptide nanofiber scaffolds for study of 3-d cell biology and beyond, Adv Cancer Res, vol.99, pp.335-62, 2008.

I. P. Witz, The selectin-selectin ligand axis in tumor progression, Cancer Metastasis Rev, vol.27, pp.19-30, 2008.

A. Klein, H. Schwartz, O. Sagi-assif, T. Meshel, S. Izraely et al., Astrocytes facilitate melanoma brain metastasis via secretion of IL-23, J Pathol, vol.236, pp.116-143, 2015.
URL : https://hal.archives-ouvertes.fr/hal-02411573

J. Bayry, E. Z. Tchilian, M. N. Davies, E. K. Forbes, S. J. Draper et al., In silico identified CCR4 antagonists target regulatory T cells and exert adjuvant activity in vaccination, Proc Natl Acad Sci, vol.105, pp.10221-10227, 2008.

H. Pere, Y. Montier, J. Bayry, F. Quintin-colonna, N. Merillon et al., A CCR4 antagonist combined with vaccines induces antigen-specific CD8+ T cells and tumor immunity against self antigens, Blood, vol.118, pp.4853-62, 2011.
URL : https://hal.archives-ouvertes.fr/pasteur-00711130

A. Muller, B. Homey, H. Soto, N. Ge, D. Catron et al., Involvement of chemokine receptors in breast cancer metastasis, Nature, vol.410, pp.50-56, 2001.

A. Zlotnik, A. M. Burkhardt, and B. Homey, Homeostatic chemokine receptors and organ-specific metastasis, Nat Rev Immunol, vol.11, pp.597-606, 2011.

A. Ben-baruch, Organ selectivity in metastasis: regulation by chemokines and their receptors, Clin Exp Metastasis, vol.25, pp.345-56, 2008.

A. D. Luster, Antichemokine immunotherapy for allergic diseases, Curr Opin Allergy Clin Immunol, vol.1, pp.561-568, 2001.

M. Gobert, I. Treilleux, N. Bendriss-vermare, T. Bachelot, S. Goddard-leon et al., Regulatory T Cells Recruited through CCL22/CCR4 Are Selectively Activated in Lymphoid Infiltrates Surrounding Primary Breast Tumors and Lead to an Adverse Clinical Outcome, Cancer Research, vol.69, pp.2000-2009, 2009.

T. J. Curiel, G. Coukos, L. H. Zou, X. Alvarez, P. Cheng et al., Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival, Nature Medicine, vol.10, pp.942-949, 2004.

R. Ueda, Clinical Application of Anti-CCR4 Monoclonal Antibody, Oncology, vol.89, pp.16-21, 2015.

J. Y. Li, Z. L. Ou, S. J. Yu, X. L. Gu, C. Yang et al., The chemokine receptor CCR4 promotes tumor growth and lung metastasis in breast cancer, Breast Cancer Res Treat, vol.131, pp.837-885, 2012.

P. B. Olkhanud, D. Baatar, M. Bodogai, F. Hakim, R. Gress et al., Breast cancer lung metastasis requires expression of chemokine receptor CCR4 and regulatory T cells, Cancer Res, vol.69, pp.5996-6004, 2009.

E. S. Nakamura, K. Koizumi, M. Kobayashi, Y. Saitoh, Y. Arita et al., RANKL-induced CCL22/macrophage-derived chemokine produced from osteoclasts potentially promotes the bone metastasis of lung cancer expressing its receptor CCR4, Clin Exp Metastasis, vol.23, pp.9-18, 2006.

B. Ou, J. Zhao, S. Guan, H. Feng, X. Wangpu et al., CCR4 promotes metastasis via ERK/NF-kappaB/MMP13 pathway and acts downstream of TNF-alpha in colorectal cancer, Oncotarget, vol.7, pp.47637-47649, 2016.

A. Aa, I. Syk, K. Jirstrom, and H. Thorlacius, CCR4 mediates CCL17 (TARC)-induced migration of human colon cancer cells via RhoA/Rho-kinase signaling, Int J Colorectal Dis, vol.28, pp.1479-87, 2013.

F. Zhu, X. Li, S. Chen, Q. Zeng, Y. Zhao et al., Tumorassociated macrophage or chemokine ligand CCL17 positively regulates the tumorigenesis of hepatocellular carcinoma, Med Oncol, vol.33, p.17, 2016.

J. Bayry, E. Tartour, and D. F. Tough, Targeting CCR4 as an emerging strategy for cancer therapy and vaccines, Trends in Pharmacological Sciences, vol.35, pp.163-165, 2014.
URL : https://hal.archives-ouvertes.fr/inserm-02455519

L. B. Liu, F. Xie, K. K. Chang, W. Q. Shang, Y. H. Meng et al., Chemokine CCL17 induced by hypoxia promotes the proliferation of cervical cancer cell, Am J Cancer Res, vol.5, pp.3072-84, 2015.

E. Lok, A. S. Chung, K. D. Swanson, and E. T. Wong, Melanoma brain metastasis globally reconfigures chemokine and cytokine profiles in patient cerebrospinal fluid, Melanoma Res, vol.24, pp.120-150, 2014.

D. , A. D. Albanesi, C. Lang, R. Girolomoni, G. Sinigaglia et al., Quantitative differences in chemokine receptor engagement generate diversity in integrin-dependent lymphocyte adhesion, J Immunol, vol.169, pp.2303-2315, 2002.

W. Berger, L. Elbling, M. Minai-pour, M. Vetterlein, R. Pirker et al., Intrinsic MDR-1 gene and P-glycoprotein expression in human melanoma cell lines, Int J Cancer, vol.59, pp.717-740, 1994.

B. B. Weksler, E. A. Subileau, N. Perriere, P. Charneau, K. Holloway et al.,

J. Greenwood, Blood-brain barrier-specific properties www.impactjournals.com/oncotarget of a human adult brain endothelial cell line, Faseb Journal, vol.19, p.1872, 2005.

M. M. Tomayko and C. P. Reynolds, Determination of subcutaneous tumor size in athymic (nude) mice, Cancer Chemother Pharmacol, vol.24, pp.148-54, 1989.

V. Harma, J. Virtanen, R. Makela, A. Happonen, J. P. Mpindi et al., A comprehensive panel of three-dimensional models for studies of prostate cancer growth, invasion and drug responses, PLoS One, vol.5, p.10431, 2010.