Journal article
Spleen Tyrosine Kinase-Mediated Autophagy Is Required for Epithelial-Mesenchymal Plasticity and Metastasis in Breast Cancer
Cancer research (Chicago, Ill.), Vol.79(8), pp.1831-1843
04/15/2019
DOI: 10.1158/0008-5472.CAN-18-2636
PMCID: PMC6467765
PMID: 30733195
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.
http://cancerres.aacrjournals.org/content/canres/79/8/1831/F1.large.jpg.
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Details
- Title: Subtitle
- Spleen Tyrosine Kinase-Mediated Autophagy Is Required for Epithelial-Mesenchymal Plasticity and Metastasis in Breast Cancer
- Creators
- Aparna Shinde - Purdue University West LafayetteShana D Hardy - Purdue University West LafayetteDongwook Kim - Purdue University West LafayetteSaeed Salehin Akhand - Purdue University West LafayetteMohit Kumar Jolly - Indian Institute of Science BangaloreWen-Hung Wang - Purdue University West LafayetteJoshua C Anderson - University of Alabama at BirminghamRyan B Khodadadi - Mayo ClinicWells S Brown - Purdue University West LafayetteJason T George - Center for Theoretical Biological PhysicsSheng Liu - Indiana UniversityJun Wan - Purdue University West LafayetteHerbert Levine - Center for Theoretical Biological PhysicsChristopher D Willey - University of Alabama at BirminghamCasey J Krusemark - Purdue University West LafayetteRobert L Geahlen - Purdue University West LafayetteMichael K Wendt - Purdue University West Lafayette
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.79(8), pp.1831-1843
- DOI
- 10.1158/0008-5472.CAN-18-2636
- PMID
- 30733195
- PMCID
- PMC6467765
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Grant note
- R01 CA207751 / NCI NIH HHS R35 GM128894 / NIGMS NIH HHS P30 CA023168 / NCI NIH HHS
- Language
- English
- Date published
- 04/15/2019
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984459634802771
Metrics
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