American Association for Cancer Research
00085472can182636-sup-207536_2_supp_5301364_pl1s5d.xlsx (16.37 kB)

Supplemental Table S1 from Spleen Tyrosine Kinase–Mediated Autophagy Is Required for Epithelial–Mesenchymal Plasticity and Metastasis in Breast Cancer

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posted on 2023-03-31, 03:08 authored by Aparna Shinde, Shana D. Hardy, Dongwook Kim, Saeed Salehin Akhand, Mohit Kumar Jolly, Wen-Hung Wang, Joshua C. Anderson, Ryan B. Khodadadi, Wells S. Brown, Jason T. George, Sheng Liu, Jun Wan, Herbert Levine, Christopher D. Willey, Casey J. Krusemark, Robert L. Geahlen, Michael K. Wendt

This table lists the GO terms associated with the genes identified to be uniquely regulated in TGF-beta induced EMT compared Lapatinib-induced EMT.


American Cancer Society






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. 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