Oncotarget

Research Papers:

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 and Tim H.-M. Huang _

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Oncotarget. 2016; 7:77124-77137. https://doi.org/10.18632/oncotarget.12808

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Abstract

Guangcun Huang1, Pawel A. Osmulski1, Hakim Bouamar2, Devalingam Mahalingam3, Chun-Lin Lin1, Michael A. Liss4, Addanki Pratap Kumar4,5, Chun-Liang Chen1, Ian M. Thompson4, Lu-Zhe Sun2, Maria E. Gaczynska1, Tim H.-M. Huang1

1Departments of Molecular Medicine Cancer Research and Therapy Center and School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA

2Departments of Cellular and Structural Biology Cancer Research and Therapy Center and School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA

3Departments of Medicine Cancer Research and Therapy Center and School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA

4Departments of Urology Cancer Research and Therapy Center and School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA

5Departments of Radiation Oncology Cancer Research and Therapy Center and School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA

Correspondence to:

Tim H.-M. Huang, email: [email protected]

Maria E. Gaczynska, email: [email protected]

Keywords: tumor metastasis, circulating tumor cells, epithelial-mesenchymal transition (EMT), transforming growth factor-β (TGF-β), positive feedback signaling

Received: August 08, 2016     Accepted: October 12, 2016     Published: October 21, 2016

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.


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