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Cancer Res. 2019 Apr 15;79(8):1831-1843. doi: 10.1158/0008-5472.CAN-18-2636. Epub 2019 Feb 7.

Spleen Tyrosine Kinase-Mediated Autophagy Is Required for Epithelial-Mesenchymal Plasticity and Metastasis in Breast Cancer.

Author information

1
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana.
2
Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana.
3
Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore, India.
4
Department of Radiation Oncology, University of Alabama, Birmingham, Alabama.
5
Department of Graduate Medical Education, Mayo Clinic, Rochester. Minnesota.
6
Center for Theoretical Biological Physics, Rice University, Houston, Texas.
7
Medical Science Training Program, Baylor College of Medicine, Houston, Texas.
8
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.
9
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana. mwendt@purdue.edu.

Abstract

The ability of breast cancer cells to transiently transition between epithelial and mesenchymal states contributes to their metastatic potential. Therefore, driving tumor cells into a stable mesenchymal state, as opposed to complete tumor cell eradication, presents an opportunity to pharmacologically limit disease progression by promoting an asymptomatic state of dormancy. Here, we compare a reversible model of epithelial-mesenchymal transition (EMT) induced by TGFβ to a stable mesenchymal phenotype induced by chronic exposure to the ErbB kinase inhibitor lapatinib. Only cells capable of returning to an epithelial phenotype resulted in skeletal metastasis. Gene expression analyses of the two mesenchymal states indicated similar transition expression profiles. A potently downregulated gene in both datasets was spleen tyrosine kinase (SYK). In contrast to this similar diminution in mRNA, kinome analyses using a peptide array and DNA-conjugated peptide substrates showed a robust increase in SYK activity upon TGFβ-induced EMT only. SYK was present in cytoplasmic RNA processing depots known as P-bodies formed during the onset of EMT, and SYK activity was required for autophagy-mediated clearance of P-bodies during mesenchymal-epithelial transition (MET). Genetic knockout of autophagy-related 7 (ATG7) or pharmacologic inhibition of SYK activity with fostamatinib, a clinically approved inhibitor of SYK, prevented P-body clearance and MET, inhibiting metastatic tumor outgrowth. Overall, this study suggests assessment of SYK activity as a biomarker for metastatic disease and the use of fostamatinib as a means to stabilize the latency of disseminated tumor cells. SIGNIFICANCE: These findings present inhibition of spleen tyrosine kinase as a therapeutic option to limit breast cancer metastasis by promoting systemic tumor dormancy.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/8/1831/F1.large.jpg.See related commentary by Farrington and Narla, p. 1756.

PMID:
30733195
PMCID:
PMC6467765
[Available on 2020-04-15]
DOI:
10.1158/0008-5472.CAN-18-2636

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