Prostate cancer cell-intrinsic interferon signaling regulates dormancy and metastatic outgrowth in bone
Loading...
Download
Associated Records
Authors
File Licence
Editors
Date
2020-06-04
Source Title
EMBO Reports
Journal Title
Journal ISSN
Volume Title
Publisher
WILEY
Affiliation
Sir Peter MacCallum Department of Oncology
Medical Biology (W.E.H.I.)
Microbiology and Immunology
Medicine (Austin & Northern Health)
Surgery (RMH)
Medical Biology (W.E.H.I.)
Microbiology and Immunology
Medicine (Austin & Northern Health)
Surgery (RMH)
Document Type
Journal Article
Subject Code
Citation
Owen, K. L., Gearing, L. J., Zanker, D. J., Brockwell, N. K., Khoo, W. H., Roden, D. L., Cmero, M., Mangiola, S., Hong, M. K., Spurling, A. J., McDonald, M., Chan, C. L., Pasam, A., Lyons, R. J., Duivenvoorden, H. M., Ryan, A., Butler, L. M., Mariadason, J. M., Giang Phan, T. ,... Parker, B. S. (2020). Prostate cancer cell-intrinsic interferon signaling regulates dormancy and metastatic outgrowth in bone. EMBO Reports, 21 (6), https://doi.org/10.15252/embr.202050162.
Access Status
Open Access
Access URL
Open Access URL
Open Access at PMC
Linked Resource URL
NHMRC Grant Code
ARC Grant Code
Description
Abstract
The latency associated with bone metastasis emergence in castrate-resistant prostate cancer is attributed to dormancy, a state in which cancer cells persist prior to overt lesion formation. Using single-cell transcriptomics and ex vivo profiling, we have uncovered the critical role of tumor-intrinsic immune signaling in the retention of cancer cell dormancy. We demonstrate that loss of tumor-intrinsic type I IFN occurs in proliferating prostate cancer cells in bone. This loss suppresses tumor immunogenicity and therapeutic response and promotes bone cell activation to drive cancer progression. Restoration of tumor-intrinsic IFN signaling by HDAC inhibition increased tumor cell visibility, promoted long-term antitumor immunity, and blocked cancer growth in bone. Key findings were validated in patients, including loss of tumor-intrinsic IFN signaling and immunogenicity in bone metastases compared to primary tumors. Data herein provide a rationale as to why current immunotherapeutics fail in bone-metastatic prostate cancer, and provide a new therapeutic strategy to overcome the inefficacy of immune-based therapies in solid cancers.