PUBLICATION
A NF-ĸB-Activin A signaling axis enhances prostate cancer metastasis
- Authors
- Chen, L., De Menna, M., Groenewoud, A., Thalmann, G.N., Kruithof-de Julio, M., Snaar-Jagalska, B.E.
- ID
- ZDB-PUB-191120-6
- Date
- 2019
- Source
- Oncogene 39(8): 1634-1651 (Journal)
- Registered Authors
- Snaar-Jagalska, Ewa B.
- Keywords
- none
- Datasets
- GEO:GSE137629
- MeSH Terms
-
- Activins/deficiency
- Activins/genetics
- Activins/metabolism*
- Animals
- Cell Proliferation
- Cell Transformation, Neoplastic
- Gene Expression Regulation, Neoplastic
- Gene Knockdown Techniques
- Humans
- Male
- Mice
- Mitogen-Activated Protein Kinase 1/metabolism
- Mitogen-Activated Protein Kinase 3/metabolism
- NF-kappa B/metabolism*
- Neoplasm Invasiveness
- Neoplasm Metastasis
- Neoplasm Staging
- Neoplastic Stem Cells/pathology
- PC-3 Cells
- Prostatic Neoplasms/metabolism
- Prostatic Neoplasms/pathology*
- Signal Transduction*
- Smad Proteins/metabolism
- Up-Regulation
- Zebrafish
- PubMed
- 31740783 Full text @ Oncogene
Citation
Chen, L., De Menna, M., Groenewoud, A., Thalmann, G.N., Kruithof-de Julio, M., Snaar-Jagalska, B.E. (2019) A NF-ĸB-Activin A signaling axis enhances prostate cancer metastasis. Oncogene. 39(8):1634-1651.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping