Pleiotrophin drives a prometastatic immune niche in breast cancer.
Ganguly, D
Schmidt, MO
Coleman, M
Ngo, T-VC
Sorrelle, N
Dominguez, ATA
Murimwa, GZ
Toombs, JE
Lewis, C
Fang, YV
Valdes-Mora, F
Gallego-Ortega, D
Wellstein, A
Brekken, RA
- Publisher:
- ROCKEFELLER UNIV PRESS
- Publication Type:
- Journal Article
- Citation:
- J Exp Med, 2023, 220, (5), pp. e20220610
- Issue Date:
- 2023-05-01
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Full metadata record
Field | Value | Language |
---|---|---|
dc.contributor.author | Ganguly, D | |
dc.contributor.author | Schmidt, MO | |
dc.contributor.author | Coleman, M | |
dc.contributor.author | Ngo, T-VC | |
dc.contributor.author | Sorrelle, N | |
dc.contributor.author | Dominguez, ATA | |
dc.contributor.author | Murimwa, GZ | |
dc.contributor.author | Toombs, JE | |
dc.contributor.author | Lewis, C | |
dc.contributor.author | Fang, YV | |
dc.contributor.author | Valdes-Mora, F | |
dc.contributor.author | Gallego-Ortega, D | |
dc.contributor.author | Wellstein, A | |
dc.contributor.author | Brekken, RA | |
dc.date.accessioned | 2024-02-29T06:39:49Z | |
dc.date.available | 2023-01-09 | |
dc.date.available | 2024-02-29T06:39:49Z | |
dc.date.issued | 2023-05-01 | |
dc.identifier.citation | J Exp Med, 2023, 220, (5), pp. e20220610 | |
dc.identifier.issn | 0022-1007 | |
dc.identifier.issn | 1540-9538 | |
dc.identifier.uri | http://hdl.handle.net/10453/175984 | |
dc.description.abstract | Metastatic cancer cells adapt to thrive in secondary organs. To investigate metastatic adaptation, we performed transcriptomic analysis of metastatic and non-metastatic murine breast cancer cells. We found that pleiotrophin (PTN), a neurotrophic cytokine, is a metastasis-associated factor that is expressed highly by aggressive breast cancers. Moreover, elevated PTN in plasma correlated significantly with metastasis and reduced survival of breast cancer patients. Mechanistically, we find that PTN activates NF-κB in cancer cells leading to altered cytokine production, subsequent neutrophil recruitment, and an immune suppressive microenvironment. Consequently, inhibition of PTN, pharmacologically or genetically, reduces the accumulation of tumor-associated neutrophils and reverts local immune suppression, resulting in increased T cell activation and attenuated metastasis. Furthermore, inhibition of PTN significantly enhanced the efficacy of immune checkpoint blockade and chemotherapy in reducing metastatic burden in mice. These findings establish PTN as a previously unrecognized driver of a prometastatic immune niche and thus represents a promising therapeutic target for the treatment of metastatic breast cancer. | |
dc.format | Print-Electronic | |
dc.language | eng | |
dc.publisher | ROCKEFELLER UNIV PRESS | |
dc.relation.ispartof | J Exp Med | |
dc.relation.isbasedon | 10.1084/jem.20220610 | |
dc.rights | info:eu-repo/semantics/openAccess | |
dc.subject | 11 Medical and Health Sciences | |
dc.subject.classification | Immunology | |
dc.subject.classification | 32 Biomedical and clinical sciences | |
dc.subject.classification | 42 Health sciences | |
dc.subject.mesh | Mice | |
dc.subject.mesh | Animals | |
dc.subject.mesh | Carrier Proteins | |
dc.subject.mesh | Neoplasms | |
dc.subject.mesh | Cytokines | |
dc.subject.mesh | NF-kappa B | |
dc.subject.mesh | Tumor Microenvironment | |
dc.subject.mesh | Animals | |
dc.subject.mesh | Mice | |
dc.subject.mesh | Neoplasms | |
dc.subject.mesh | Carrier Proteins | |
dc.subject.mesh | NF-kappa B | |
dc.subject.mesh | Cytokines | |
dc.subject.mesh | Tumor Microenvironment | |
dc.subject.mesh | Mice | |
dc.subject.mesh | Animals | |
dc.subject.mesh | Carrier Proteins | |
dc.subject.mesh | Neoplasms | |
dc.subject.mesh | Cytokines | |
dc.subject.mesh | NF-kappa B | |
dc.subject.mesh | Tumor Microenvironment | |
dc.title | Pleiotrophin drives a prometastatic immune niche in breast cancer. | |
dc.type | Journal Article | |
utslib.citation.volume | 220 | |
utslib.location.activity | United States | |
utslib.for | 11 Medical and Health Sciences | |
pubs.organisational-group | University of Technology Sydney | |
pubs.organisational-group | University of Technology Sydney/Faculty of Engineering and Information Technology | |
pubs.organisational-group | University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering | |
pubs.organisational-group | University of Technology Sydney/Centre for Health Technologies (CHT) | |
utslib.copyright.status | open_access | * |
dc.date.updated | 2024-02-29T06:39:40Z | |
pubs.issue | 5 | |
pubs.publication-status | Published | |
pubs.volume | 220 | |
utslib.citation.issue | 5 |
Abstract:
Metastatic cancer cells adapt to thrive in secondary organs. To investigate metastatic adaptation, we performed transcriptomic analysis of metastatic and non-metastatic murine breast cancer cells. We found that pleiotrophin (PTN), a neurotrophic cytokine, is a metastasis-associated factor that is expressed highly by aggressive breast cancers. Moreover, elevated PTN in plasma correlated significantly with metastasis and reduced survival of breast cancer patients. Mechanistically, we find that PTN activates NF-κB in cancer cells leading to altered cytokine production, subsequent neutrophil recruitment, and an immune suppressive microenvironment. Consequently, inhibition of PTN, pharmacologically or genetically, reduces the accumulation of tumor-associated neutrophils and reverts local immune suppression, resulting in increased T cell activation and attenuated metastasis. Furthermore, inhibition of PTN significantly enhanced the efficacy of immune checkpoint blockade and chemotherapy in reducing metastatic burden in mice. These findings establish PTN as a previously unrecognized driver of a prometastatic immune niche and thus represents a promising therapeutic target for the treatment of metastatic breast cancer.
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