| Title: |
Prostate cancer cell-intrinsic interferon signaling regulates dormancy and metastatic outgrowth in bone |
| Authors: |
Owen, KL; Gearing, LJ; Zanker, DJ; Brockwell, NK; Khoo, WH; Roden, DL; Cmero, M; Mangiola, S; Hong, MK; Spurling, AJ; McDonald, M; Chan, CL; Pasam, A; Lyons, RJ; Duivenvoorden, HM; Ryan, A; Butler, LM; Mariadason, JM; Giang Phan, T; Hayes, VM; Sandhu, S; Swarbrick, A; Corcoran, NM; Hertzog, PJ; Croucher, PI; Hovens, C; Parker, BS |
| Publisher Information: |
WILEY |
| Publication Year: |
2020 |
| Collection: |
The University of Melbourne: Digital Repository |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| ISSN: |
1469-221X |
| Relation: |
https://hdl.handle.net/11343/246112 |
| Availability: |
https://hdl.handle.net/11343/246112 |
| Rights: |
https://creativecommons.org/licenses/by-nc-nd/4.0 ; CC BY-NC-ND |
| Accession Number: |
edsbas.485CC40F |
| Database: |
BASE |