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.
Highlights
Prostate cancer is the third most commonly diagnosed cancer in the United States with an estimated 220,800 new cases and 27,540 deaths in 2015 [1]
While the TGFBRII-editing resulted in disruption of signaling network traffic for transforming growth factor-β (TGF-β)-driven epithelial-mesenchymal transition (EMT), we found that the disturbance triggered a feedback mechanism by activating extracellular signal-regulated kinase (ERK) for supporting EMT-mediated metastasis
We conducted a comparative study of TGF-βdriven EMT in cultured CRPC cells and in circulating tumor cells (CTCs) and the enumeration of CTCs and accompanying host macrophages isolated from xenograft hosts and prostate cancer patients, respectively (Supplementary Figure S1)
Summary
Prostate cancer is the third most commonly diagnosed cancer in the United States with an estimated 220,800 new cases and 27,540 deaths in 2015 [1]. Androgen-deprivation therapy remains the principal treatment for patients with biochemical recurrence; some patients eventually develop metastatic castration-resistant prostate cancer (mCRPC) with malignant lesions detected in distant organs including bones [2]. Additional treatments, such as chemotherapy and target therapy, are needed for CRPC patients. The development of mCRPC is multifaceted, and the underlying mechanism remains elusive. Emerging evidence indicates that epithelial-to-mesenchymal transition (EMT) is a critical process to promote cancer invasion and metastasis including mCRPC [4, 5]
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