TGF-β signal rewiring sustains epithelial-mesenchymal transition of circulating tumor cells in prostate cancer xenograft hosts

Guangcun Huang, Pawel A. Osmulski, Hakim Bouamar, Devalingam Mahalingam, Chun Lin Lin, Michael A. Liss, Addanki Pratap Kumar, Chun Liang Chen, Ian M. Thompson, Lu Zhe Sun, Maria E. Gaczynska, Tim H.M. Huang

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Activation of TGF-β signaling is known to promote epithelial-mesenchymal transition (EMT) for the development of metastatic castration-resistant prostate cancer (mCRPC). To determine whether targeting TGF-β 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-β signaling in mCRPC cells. As a result, the delicate balance of oncogenic homeostasis is perturbed, profoundly uncoupling proliferative and metastatic potential of TGFBRII-edited 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-β and its backup partner ERK represents an attractive strategy for treating mCRPC patients.

Original languageEnglish (US)
Pages (from-to)77124-77137
Number of pages14
JournalOncotarget
Volume7
Issue number47
DOIs
StatePublished - 2016

Keywords

  • Circulating tumor cells
  • Epithelial-mesenchymal transition (EMT)
  • Positive feedback signaling
  • Transforming growth factor-β (TGF-β)
  • Tumor metastasis

ASJC Scopus subject areas

  • Oncology

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