Journal
ONCOTARGET
Volume 7, Issue 47, Pages 77124-77137Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.12808
Keywords
tumor metastasis; circulating tumor cells; epithelial-mesenchymal transition (EMT); transforming growth factor-beta (TGF-beta); positive feedback signaling
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Funding
- NIH [R01CA172886, U54CA113001, P30CA054174]
- Cancer Prevention and Research Institute of Texas (CPRIT) [RP150600]
- Max and Minnie Tomerlin Voelcker Fund
- Cancer Therapy and Research Center Foundation
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Activation of TGF-beta signaling is known to promote epithelial-mesenchymal transition (EMT) for the development of metastatic castration-resistant prostate cancer (mCRPC). To determine whether targeting TGF-beta signaling alone is sufficient to mitigate mCRPC, we used the CRISPR/Cas9 genome-editing approach to generate a dominant-negative mutation of the cognate receptor TGFBRII that attenuated TGF-beta signaling in mCRPC cells. As a result, the delicate balance of oncogenic homeostasis is perturbed, profoundly uncoupling proliferative and metastatic potential of TGFBRIIedited tumor xenografts. This signaling disturbance triggered feedback rewiring by enhancing ERK signaling known to promote EMT-driven metastasis. Circulating tumor cells displaying upregulated EMT genes had elevated biophysical deformity and an increase in interactions with chaperone macrophages for facilitating metastatic extravasation. Treatment with an ERK inhibitor resulted in decreased aggressive features of CRPC cells in vitro. Therefore, combined targeting of TGF-beta and its backup partner ERK represents an attractive strategy for treating mCRPC patients.
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