Journal of Cancer Stem Cell Research

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Platelet Derived Growth Factor Receptor-b (PDGFRb) Signaling: A Novel Therapeutic Target for Breast Cancer Associated Brain Metastasis

Journal of Cancer Stem Cell Research

Abstract

PDGFRb 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 PDGFRb and PDGFB has been noted in patient breast tumors for decades, how
PDGFB-to-PDGFRb tumor-stromal signaling mediates breast cancer initiation, progression, and metastasis remains unclear. To
test this important research question, we developed a mouse model of mesenchymal-specific PDGFRb hyper-activation.
PDGFRb mutant mammary glands exhibit increased tertiary side-branching and epithelial proliferation confirming a stromalspecific
PDGFRb effect on neighboring epithelium during normal development. To test the effect of hyper-active mesenchymal
PDGFRb on tumor progression, orthotopicmammarytumor growth wasevaluated. Interestingly, whileweobserved no significant
difference in primary tumor growth, the incidence of brain metastases from the orthotopic site was significantly increased in the
mutant animals. These findings were confirmed using experimental tail vein metastasis assays wherewealso observed prominent
brain metastases in 50% of the PDGFRb mutant mice (n ¼ 5/10) with no brain lesions seen in controls (n ¼ 0/19). In both the
orthotopic and tail vein assays, there was no difference in the incidence of lung or liver metastases in the mutant mice suggesting a
pro-metastatic function for PDGFRb in the brain metastatic niche. To rule out dysfunction of the blood brain barrier contributing to
the observed metastatic spread, we then intracranially injected mammary tumor cells, and as expected based on our metastasis
assay, found that larger tumors formed in the brains of PDGFRb mutant mice versus controls. To our knowledge, these combined
findings are the first example where genetic manipulation of the stroma increases breast cancer associated brain metastases
(BCBM). Given that these pre-clinical data suggest that primary breast tumors expressing high PDGFB could preferentially
metastasize to the brain, we analyzed PDGFB protein expression in a tissue microarray comprised of HER2-positive and triple
negative breast cancer (TNBC) primary tumors (total n ¼ 425). While high PDGFB did not correlate with site-independent
metastatic recurrence, it was prognostic of brain metastasis, mirroring our mouse data. Evaluation of PDGFB in a small cohort of
matched primary breast tumors with associated brain (n¼5) and lung metastases (n¼2) revealed intensePDGFBstaining in 100%
of the brain metastases, but only 50% of the lung metastases. These findings further suggest that high primary tumor PDGFB
expression defines a subset of breast cancer patients predisposed to brain metastases and that these patients may benefit from
therapeutic inhibition of PDGFRb signaling. To test this pre-clinically, we treated mice harboring intracranial tumors with the
PDGFR specific inhibitor crenolanib. Excitingly, crenolanib treatment significantly inhibited the brain tumor burden in these mice.
Combined, our findings to date (1) advocate that primary tumor expression of PDGFB is a novel prognostic biomarker for the
development of BCBM and (2) support clinical trial evaluation of PDGFR inhibitors for the prevention and treatment of BCBM.
Ongoing studies are evaluating howthePDGFRb-expressing mesenchymal cells within the brain promote a pro-metastatic niche.
Keywords: PDGFRb, PDGF-B, Tumor microenvironment, Breast cancer.

  • Anisha M. Hammer, Katie A. Thies, Blake E. Hildreth III, Luke O. Russell, Steven T. Sizemore, Anthony J. Trimboli, Raleigh D. Kladney, Sarah A. Steck1, Manjusri Das, Chelsea M. Bolyard, Robert Pilarski, Lynn Schoenfield, Jose Otero, Arnab Chakravarti ...
  • Journal of Cancer Stem Cell Research 2019, 6:e1001 (January 02, 2019)
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  • DOI: 10.14343/JCSCR.2018.6e1001

Editors-In-Chief

Pranela Rameshwar, Ph.D.
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Mariusz Ratajczak, M.D., Ph.D. ...
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Justin Lathia, Ph.D.
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