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Stromal Platelet–Derived Growth Factor Receptor-β Signaling Promotes Breast Cancer Metastasis in the Brain

Authors: Thies, Katie A.; Hammer, Anisha M.; Hildreth, Blake E.; Steck, Sarah A.; Spehar, Jonathan M.; Kladney, Raleigh D.; Geisler, Jennifer M.; Das, Manjusri; Russell, Luke O.; Bey, Jerome F.; Bolyard, Chelsea M.; Pilarski, Robert; Trimboli, Anthony J.; Cuitiño, Maria C.; Koivisto, Christopher S.; Stover, Daniel G.; Schoenfield, Lynn; Otero, Jose; Godbout, Jonathan; Chakravarti, Arnab; Ringel, Matthew D.; Ramaswamy, Bhuvaneswari; Li, Zaibo; Kaur, Balveen; Leone, Gustavo; Ostrowski, Michael C.; Sizemore, Steven T.; Sizemore, Gina M.

Online: http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=32327406

Issue: Cancer Res. 2020 Apr 23;10.1158/0008-5472.CAN-19-3731.


Platelet-derived growth factor receptor-beta (PDGFRβ) is a receptor tyrosine kinase found in cells of mesenchymal origin such as fibroblasts and pericytes. Activation of this receptor is dependent on paracrine ligand induction, and its preferred ligand PDGFB is released by neighboring epithelial and endothelial cells. While expression of both PDGFRβ and PDGFB has been noted in patient breast tumors for decades, how PDGFB-to-PDGFRβ tumor-stroma signaling mediates breast cancer initiation, progression, and metastasis remains unclear. Here we demonstrate this paracrine signaling pathway mediates both primary tumor growth and metastasis, specifically, metastasis to the brain. Elevated levels of PDGFB accelerated orthotopic tumor growth and intracranial growth of mammary tumor cells, while mesenchymal-specific expression of an activating mutant PDGFRβ (PDGFRβD849V) exerted proproliferative signals on adjacent mammary tumor cells. Stromal expression of PDGFRβD849V also promoted brain metastases of mammary tumor cells expressing high PDGFB when injected intravenously. In the brain, expression of PDGFRβD849V was observed within a subset of astrocytes, and aged mice expressing PDGFRβD849V exhibited reactive gliosis. Importantly, the PDGFR-specific inhibitor crenolanib significantly reduced intracranial growth of mammary tumor cells. In a tissue microarray comprised of 363 primary human breast tumors, high PDGFB protein expression was prognostic for brain metastases, but not metastases to other sites. Our results advocate the use of mice expressing PDGFRβD849V in their stromal cells as a preclinical model of breast cancer-associated brain metastases and support continued investigation into the clinical prognostic and therapeutic use of PDGFB-to-PDGFRβ signaling in women with breast cancer. SIGNIFICANCE: These studies reveal a previously unknown role for PDGFB-to-PDGFRβ paracrine signaling in the promotion of breast cancer brain metastases and support the prognostic and therapeutic clinical utility of this pathway for patients.