Spleen Tyrosine Kinase–Mediated Autophagy Is Required for Epithelial–Mesenchymal Plasticity and Metastasis in Breast Cancer
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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. See related commentary by Farrington and Narla, p. 1756
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Both fostamatinib and colchicine have shown antitumor and anti-metastasis effects in animal models of breast cancer.
“Both fostamatinib and colchicine have shown antitumor and anti-metastasis effects in animal models of breast cancer34,35.”
From ASGARD is a single-cell guided pipeline to aid repurposing of drugs (2023) · cites this paper as [35]
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- Authors
- Shinde, A., Hardy, S. D., Kim, D., Akhand, S. S., Jolly, M. K., Wang, W.-H., Anderson, J. C., Khodadadi, R. B., Brown, W. S., George, J. T., Liu, S., Wan, J., Levine, H., Willey, C. D., Krusemark, C. J., Geahlen, R. L., & Wendt, M. K.
- Affiliations
- Purdue University West Lafayette (US)
- 1Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana.
- Indian Institute of Science Bangalore (IN)
- University of Alabama at Birmingham (US)
- Mayo Clinic (US)
- Baylor College of Medicine (US)
- Center for Theoretical Biological Physics (US)
- Corresponding author
- Wendt, Michael K.
- ORCID
- Venue
- Cancer Research
- Published
- 2019-04-15
- Volume
- 79
- Issue
- 8
- Pages
- 1831-1843
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC6467765
- OpenAlex
- W2911423692
- Cited by
- 115
- References
- 47
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 9 · 2023: 14 · 2022: 10 · 2021: 27 · 2020: 39 · 2019: 6
- FWCI
- 8.67
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- NOT FOUND REPOSITORY (Indian Institute of Science Bangalore) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Purdue University Indianapolis (Indiana University) (submittedVersion)
- PMC
- Funders
- American Cancer Society (RSG-CSM130259)
- NIH (R01CA207751, RO1AI098132)
- NIH NCI (30CA023168)
- CPRIT (RP170593)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- Syk, autophagy, epithelial-mesenchymal transition, epithelial-mesenchymal plasticity, breast cancer metastasis, P-bodies, fostamatinib, ATG7, TGF-beta, lapatinib, metastatic dormancy, disseminated tumor cells
- MeSH terms
- Syk Kinase, Autophagy, Breast Neoplasms, Humans, Transforming Growth Factor beta, Epithelial-Mesenchymal Transition
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