PMID- 35980743
OWN - NLM
STAT- MEDLINE
DCOM- 20220909
LR  - 20221009
IS  - 2379-3708 (Electronic)
IS  - 2379-3708 (Linking)
VI  - 7
IP  - 17
DP  - 2022 Sep 8
TI  - MCP-1/CCR2 axis inhibition sensitizes the brain microenvironment against melanoma 
      brain metastasis progression.
LID - 10.1172/jci.insight.154804 [doi]
LID - e154804
AB  - Development of resistance to chemo- and immunotherapies often occurs following 
      treatment of melanoma brain metastasis (MBM). The brain microenvironment (BME), 
      particularly astrocytes, cooperate toward MBM progression by upregulating 
      secreted factors, among which we found that monocyte chemoattractant protein-1 
      (MCP-1) and its receptors, CCR2 and CCR4, were overexpressed in MBM compared with 
      primary lesions. Among other sources of MCP-1 in the brain, we show that melanoma 
      cells altered astrocyte secretome and evoked MCP-1 expression and secretion, 
      which in turn induced CCR2 expression in melanoma cells, enhancing in vitro 
      tumorigenic properties, such as proliferation, migration, and invasion of 
      melanoma cells. In vivo pharmacological blockade of MCP-1 or molecular knockout 
      of CCR2/CCR4 increased the infiltration of cytotoxic CD8+ T cells and attenuated 
      the immunosuppressive phenotype of the BME as shown by decreased infiltration of 
      Tregs and tumor-associated macrophages/microglia in several models of 
      intracranially injected MBM. These in vivo strategies led to decreased MBM 
      outgrowth and prolonged the overall survival of the mice. Our findings highlight 
      the therapeutic potential of inhibiting interactions between BME and melanoma 
      cells for the treatment of this disease.
FAU - Pozzi, Sabina
AU  - Pozzi S
AD  - Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv 
      University, Tel Aviv, Israel.
FAU - Scomparin, Anna
AU  - Scomparin A
AD  - Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv 
      University, Tel Aviv, Israel.
AD  - Department of Drug Science and Technology, University of Turin, Turin, Italy.
FAU - Ben-Shushan, Dikla
AU  - Ben-Shushan D
AD  - Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv 
      University, Tel Aviv, Israel.
FAU - Yeini, Eilam
AU  - Yeini E
AD  - Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv 
      University, Tel Aviv, Israel.
FAU - Ofek, Paula
AU  - Ofek P
AD  - Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv 
      University, Tel Aviv, Israel.
FAU - Nahmad, Alessio D
AU  - Nahmad AD
AD  - The School of Neurobiology, Biochemistry and Biophysics, The George S. Wise 
      Faculty of Life Sciences, and.
AD  - Dotan Center for Advanced Therapies, Tel Aviv Sourasky Medical Center (TASMC), 
      Tel Aviv University, Tel Aviv, Israel.
FAU - Soffer, Shelly
AU  - Soffer S
AD  - Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv 
      University, Tel Aviv, Israel.
FAU - Ionescu, Ariel
AU  - Ionescu A
AD  - Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv 
      University, Tel Aviv, Israel.
FAU - Ruggiero, Antonella
AU  - Ruggiero A
AD  - Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv 
      University, Tel Aviv, Israel.
FAU - Barzel, Adi
AU  - Barzel A
AD  - The School of Neurobiology, Biochemistry and Biophysics, The George S. Wise 
      Faculty of Life Sciences, and.
AD  - Dotan Center for Advanced Therapies, Tel Aviv Sourasky Medical Center (TASMC), 
      Tel Aviv University, Tel Aviv, Israel.
FAU - Brem, Henry
AU  - Brem H
AD  - Department of Neurosurgery, Johns Hopkins University School of Medicine, 
      Baltimore, Maryland, USA.
FAU - Hyde, Thomas M
AU  - Hyde TM
AD  - Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, 
      Maryland, USA.
FAU - Barshack, Iris
AU  - Barshack I
AD  - Department of Pathology, Sheba Medical Center, Tel Hashomer, Israel.
AD  - Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel 
      Aviv, Israel.
FAU - Sinha, Sanju
AU  - Sinha S
AD  - Cancer Data Science Laboratory, Center for Cancer Research, National Cancer 
      Institute, NIH, Bethesda, Maryland, USA.
FAU - Ruppin, Eytan
AU  - Ruppin E
AD  - Cancer Data Science Laboratory, Center for Cancer Research, National Cancer 
      Institute, NIH, Bethesda, Maryland, USA.
FAU - Weiss, Tomer
AU  - Weiss T
FAU - Madi, Asaf
AU  - Madi A
FAU - Perlson, Eran
AU  - Perlson E
AD  - Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv 
      University, Tel Aviv, Israel.
AD  - Department of Pathology, Sackler Faculty of Medicine, and.
FAU - Slutsky, Inna
AU  - Slutsky I
AD  - Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv 
      University, Tel Aviv, Israel.
AD  - Department of Pathology, Sackler Faculty of Medicine, and.
FAU - Florindo, Helena F
AU  - Florindo HF
AD  - Sagol School of Neurosciences, Tel Aviv University, Tel Aviv, Israel.
FAU - Satchi-Fainaro, Ronit
AU  - Satchi-Fainaro R
AD  - Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv 
      University, Tel Aviv, Israel.
AD  - Department of Pathology, Sackler Faculty of Medicine, and.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220908
PL  - United States
TA  - JCI Insight
JT  - JCI insight
JID - 101676073
RN  - 0 (Ccr2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Receptors, CCR2)
SB  - IM
MH  - Animals
MH  - Brain/metabolism
MH  - *Brain Neoplasms/drug therapy/secondary
MH  - Chemokine CCL2/metabolism
MH  - *Melanoma/drug therapy/pathology
MH  - Mice
MH  - Receptors, CCR2/metabolism
MH  - Tumor Microenvironment
PMC - PMC9536270
OTO - NOTNLM
OT  - Cancer immunotherapy
OT  - Oncology
OT  - Skin cancer
OT  - Therapeutics
COIS- Conflict of interest: HB is a consultant for AsclepiX Therapeutics, Perosphere 
      Inc./AMAG Pharmaceuticals, Inc.; StemGen; InSightec; Accelerating Combination 
      Therapies; Camden Partners; LikeMinds, Inc.; Galen Robotics, Inc.; Nurami 
      Medical; and B*CURED. RSF is on the Board of Directors at Teva Pharmaceutical 
      Industries Ltd.
EDAT- 2022/08/19 06:00
MHDA- 2022/09/11 06:00
PMCR- 2022/09/08
CRDT- 2022/08/18 12:02
PHST- 2021/09/08 00:00 [received]
PHST- 2022/07/27 00:00 [accepted]
PHST- 2022/08/19 06:00 [pubmed]
PHST- 2022/09/11 06:00 [medline]
PHST- 2022/08/18 12:02 [entrez]
PHST- 2022/09/08 00:00 [pmc-release]
AID - 154804 [pii]
AID - 10.1172/jci.insight.154804 [doi]
PST - epublish
SO  - JCI Insight. 2022 Sep 8;7(17):e154804. doi: 10.1172/jci.insight.154804.