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Please use this identifier to cite or link to this item: http://repository.iitr.ac.in/handle/123456789/20075
Title: Δnp63-driven recruitment of myeloid-derived suppressor cells promotes metastasis in triple-negative breast cancer
Authors: Kumar, Sushil
Wilkes D.W.
Samuel N.
Blanco M.A.
Nayak A.
Alicea-Torres K.
Gluck C.
Sinha S.
Gabrilovich D.
Chakrabarti R.
Published in: Journal of Clinical Investigation
Abstract: Triple-negative breast cancer (TNBC) is particularly aggressive, with enhanced incidence of tumor relapse, resistance to chemotherapy, and metastases. As the mechanistic basis for this aggressive phenotype is unclear, treatment options are limited. Here, we showed an increased population of myeloid-derived immunosuppressor cells (MDSCs) in TNBC patients compared with non-TNBC patients. We found that high levels of the transcription factor ΔNp63 correlate with an increased number of MDSCs in basal TNBC patients, and that ΔNp63 promotes tumor growth, progression, and metastasis in human and mouse TNBC cells. Furthermore, we showed that MDSC recruitment to the primary tumor and metastatic sites occurs via direct ΔNp63-dependent activation of the chemokines CXCL2 and CCL22. CXCR2/CCR4 inhibitors reduced MDSC recruitment, angiogenesis, and metastasis, highlighting a novel treatment option for this subset of TNBC patients. Finally, we found that MDSCs secrete prometastatic factors such as MMP9 and chitinase 3-like 1 to promote TNBC cancer stem cell function, thereby identifying a nonimmunologic role for MDSCs in promoting TNBC progression. These findings identify a unique crosstalk between ΔNp63+ TNBC cells and MDSCs that promotes tumor progression and metastasis, which could be exploited in future combined immunotherapy/chemotherapy strategies for TNBC patients. © 2018 American Society for Clinical Investigation. All rights reserved.
Citation: Journal of Clinical Investigation, 128(11): 5095-5109
URI: https://doi.org/10.1172/JCI99673
http://repository.iitr.ac.in/handle/123456789/20075
Issue Date: 2018
Publisher: American Society for Clinical Investigation
Keywords: CD34 antigen
chemokine receptor CCR4
chemokine receptor CXCR2
chitinase 3 like protein 1
CXCL2 chemokine
gelatinase B
genomic DNA
macrophage derived chemokine
platelet endothelial cell adhesion molecule 1
smooth muscle actin
transcription factor
transcription factor np63
unclassified drug
CCL22 protein, human
CCR4 protein, human
chemokine receptor CCR4
chemokine receptor CXCR4
CHI3L1 protein, human
chitinase 3 like protein 1
CXCL2 chemokine
CXCL2 protein, human
CXCR4 protein, human
gelatinase B
macrophage derived chemokine
MMP9 protein, human
TP63 protein, human
transcription factor
tumor suppressor protein
angiogenesis
animal cell
animal experiment
animal model
Article
bone metastasis
cancer stem cell
carcinogenic activity
cell count
cell fate
cell infiltration
cell proliferation
chemotaxis assay
coculture
comparative study
controlled study
distant metastasis free survival
enzyme linked immunosorbent assay
human
human cell
human tissue
immunofluorescence test
immunohistochemistry
lung metastasis
lung nodule
metastasis
mitosis index
monolayer culture
mouse
myeloid-derived suppressor cell
nonhuman
primary tumor
priority journal
protein expression
spleen size
supernatant
triple negative breast cancer
tumor growth
tumor invasion
tumor xenograft
animal
Bagg albino mouse
female
genetics
immunology
MCF-7 cell line
metastasis
myeloid-derived suppressor cell
nude mouse
pathology
triple negative breast cancer
Animals
Chemokine CCL22
Chemokine CXCL2
Chitinase-3-Like Protein 1
Female
Humans
Matrix Metalloproteinase 9
MCF-7 Cells
Mice
Mice, Inbred BALB C
Mice, Nude
Myeloid-Derived Suppressor Cells
Neoplasm Metastasis
Neoplastic Stem Cells
Receptors, CCR4
Receptors, CXCR4
Transcription Factors
Triple Negative Breast Neoplasms
Tumor Suppressor Proteins
ISSN: 219738
Author Scopus IDs: 57213855617
57204506232
57204495772
56733790800
57197505535
57200032589
57188560479
7403739042
7005489089
16149432900
Author Affiliations: Kumar, S., Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, 380 S. University Avenue, 411 Hill Pavilion, Philadelphia, PA 19104, United States
Wilkes, D.W., Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, 380 S. University Avenue, 411 Hill Pavilion, Philadelphia, PA 19104, United States
Samuel, N., Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, 380 S. University Avenue, 411 Hill Pavilion, Philadelphia, PA 19104, United States
Blanco, M.A., Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, 380 S. University Avenue, 411 Hill Pavilion, Philadelphia, PA 19104, United States
Nayak, A., Department of Pathology, Laboratory Medicine, Hospital of the University of Pennsylvania, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
Alicea-Torres, K., Wistar Institute, Philadelphia, PA, United States
Gluck, C., Department of Biochemistry, State University of New York, Buffalo, NY, United States
Sinha, S., Department of Biochemistry, State University of New York, Buffalo, NY, United States
Gabrilovich, D., Wistar Institute, Philadelphia, PA, United States
Chakrabarti, R., Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, 380 S. University Avenue, 411 Hill Pavilion, Philadelphia, PA 19104, United States
Funding Details: We thank Serge Y. Fuchs, Ellen Puré, Oliver A. Garden, Manti Guha, and Leslie King (University of Pennsylvania) for critical reading of the manuscript and helpful discussions. We thank the Penn Vet Comparative Pathology Core for their assistance with embedding and sectioning of tumor samples. We thank the Eastern Division of the Cooperative Human Tissue Network, University of Pennsylvania, for providing human breast cancer fixed tissues from patients. We thank the members of Flow Cytometry Core at the Children’s Hospital of Philadelphia and the University of Pennsylvania. This work was supported by grants from the American Cancer Society and the McCabe Fund Fellow Award from the University of Pennsylvania (to RC) as well as an NCI K22 grant (K22CA193661 to RC). American Cancer Society, ACS; National Cancer Institute, NCI: K22CA193661; University of Pennsylvania, Penn
Corresponding Author: Chakrabarti, R.; Department of Biomedical Sciences, 380 S. University Avenue, 411 Hill Pavilion, United States; email: rumela@vet.upenn.edu
Appears in Collections:Journal Publications [BT]

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