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

Chen, Lanpeng; De Menna, Marta; Groenewoud, Arwin; Thalmann, George N.; Kruithof-de Julio, Marianna; Snaar-Jagalska, B Ewa (2020). A NF-ĸB-Activin A signaling axis enhances prostate cancer metastasis. Oncogene, 39(8), pp. 1634-1651. Springer Nature 10.1038/s41388-019-1103-0

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Urologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Urologie

04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Urology

UniBE Contributor:

De Menna, Marta; Thalmann, George and Kruithof-de Julio, Marianna

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1476-5594

Publisher:

Springer Nature

Language:

English

Submitter:

Jeannine Wiemann

Date Deposited:

17 Jan 2020 13:49

Last Modified:

23 Feb 2020 01:34

Publisher DOI:

10.1038/s41388-019-1103-0

PubMed ID:

31740783

BORIS DOI:

10.7892/boris.137275

URI:

https://boris.unibe.ch/id/eprint/137275

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