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A NF-ĸB-Activin A signaling axis enhances prostate cancer metastasis

Oncogene volume 39, pages 1634–1651 (2020)Cite this article

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Abstract

Metastasis is a main cause of death in prostate cancer (PCa). To dissect the molecular cues from cancer cell–microenvironment interaction that drive metastatic cascade, bone metastatic PCa cells were intravenously implanted into zebrafish embryos and mice tibia forming metastatic lesions. Transcriptomic analysis showed an elevated expression of stemness genes, pro-inflammatory cytokines and TGF-β family member Activin A in the cancer cells at metastatic onset in both animal models. Consistently, analysis of clinical datasets revealed that the expression of Activin A is specifically elevated in metastases and correlates with poor prognosis in stratified high-risk PCa patients. It is further unveiled that the microenvironment induced Activin A expression by NF-κB activation. The elevated level of Activin A enhanced the invasive ALDHhi CSC-like phenotypes and PCa proliferation by activation of Smad and ERK1/2 signaling driving metastasis. Suppression of Activin A or Activin receptor significantly reduced the CSC-like subpopulation, invasion, metastatic growth, and bone lesion formation in zebrafish and mice xenografts, suggesting a functional role of NF-κB-dependent Activin A in PCa metastasis. Overall, our study demonstrates that human PCa cells can display a comparable response with the microenvironment in zebrafish and mice xenografts. Combining both animal models, we uncovered the microenvironment-dependent activin signaling as an essential driver in PCa metastasis with therapeutic potential.

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Acknowledgements

We thank Dr Gabriel van der Pluijm (Deportment of Urology, LUMC) for providing experimental material, Prof. Peter ten Dijke (Department of Molecular Cell Biology) for providing experimental material and critical scientific discussion and Guido de Roo from the Flow cytometry facility (Department of Hematology, LUMC) for technical support, Prof. Rob Hoeben and Martijn Rabelink (Department of Cell Biology, LUMC) for providing lentiviral shRNA vectors (Sigma-Aldrich). The present work was supported by a personalized medicine grant from Alpe D’HuZes (AdH)/KWF PROPER entitled “Near-patient prostate cancer models for the assessment of disease prognosis and therapy” (UL2014-7058) and SNF 31003A_169352.

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  1. Institute of Biology, University of Leiden, Leiden, Netherlands

    Lanpeng Chen, Arwin Groenewoud & B. Ewa Snaar-Jagalska

  2. Department of BioMedical Research, Urology Research Laboratory, University of Bern, Bern, Switzerland

    Marta De Menna & Marianna Kruithof-de Julio

  3. Department of Urology, Inselspital, Bern, Switzerland

    George N. Thalmann

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Chen, L., De Menna, M., Groenewoud, A. et al. A NF-ĸB-Activin A signaling axis enhances prostate cancer metastasis. Oncogene 39, 1634–1651 (2020). https://doi.org/10.1038/s41388-019-1103-0

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