Age-associated microenvironmental changes highlight the role of PDGF-C in ER+ breast cancer metastatic relapse.
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Embargo End Date
ICR Authors
Authors
Turrell, FK
Orha, R
Guppy, NJ
Gillespie, A
Guelbert, M
Starling, C
Haider, S
Isacke, CM
Orha, R
Guppy, NJ
Gillespie, A
Guelbert, M
Starling, C
Haider, S
Isacke, CM
Document Type
Journal Article
Date
2023-04-01
Date Accepted
2023-02-07
Abstract
Patients with estrogen receptor (ER)-positive breast cancer are at risk of metastatic relapse for decades after primary tumor resection and treatment, a consequence of dormant disseminated tumor cells (DTCs) reawakening at secondary sites. Here we use syngeneic ER+ mouse models in which DTCs display a dormant phenotype in young mice but accelerated metastatic outgrowth in an aged or fibrotic microenvironment. In young mice, low-level Pdgfc expression by ER+ DTCs is required for their maintenance in secondary sites but is insufficient to support development of macrometastases. By contrast, the platelet-derived growth factor (PDGF)-Chi environment of aging or fibrotic lungs promotes DTC proliferation and upregulates tumor cell Pdgfc expression stimulating further stromal activation, events that can be blocked by pharmacological inhibition of PDGFRα or with a PDGF-C-blocking antibody. These results highlight the role of the changing microenvironment in regulating DTC outgrowth and the opportunity to target PDGF-C signaling to limit metastatic relapse in ER+ breast cancer.
Citation
Nature Cancer, 2023, 4 (4), pp. 468 - 484
Source Title
Nature Cancer
Publisher
NATURE PORTFOLIO
ISSN
2662-1347
eISSN
2662-1347
2662-1347
2662-1347
Collections
Research Team
BCR Bioinformatics Group
Molecular Cell Biology
Molecular Cell Biology