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Title: Prostate cancer cell-intrinsic interferon signaling regulates dormancy and metastatic outgrowth in bone.
Austin Authors: Owen, Katie L;Gearing, Linden J;Zanker, Damien J;Brockwell, Natasha K;Khoo, Weng Hua;Roden, Daniel L;Cmero, Marek;Mangiola, Stefano;Hong, Matthew K;Spurling, Alex J;McDonald, Michelle;Chan, Chia-Ling;Pasam, Anupama;Lyons, Ruth J;Duivenvoorden, Hendrika M;Ryan, Andrew;Butler, Lisa M;Mariadason, John M ;Giang Phan, Tri;Hayes, Vanessa M;Sandhu, Shahneen;Swarbrick, Alexander;Corcoran, Niall M;Hertzog, Paul J;Croucher, Peter I;Hovens, Chris;Parker, Belinda S
Affiliation: Murdoch Children's Research Institute, Parkville, Victoria, Australia
St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia
Division of Bone Biology, Garvan Institute of Medical Research, Sydney, NSW, Australia
School of Biotechnology and Biomolecular Sciences, UNSW Sydney, Sydney, NSW, Australia
Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia
Cancer Immunology and Therapeutics Programs, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
TissuePath Specialist Pathology, Mount Waverley, Vic, Australia
Translational Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
Bioinformatics Division, The Walter and Eliza Hall Institute, Parkville, Victoria, Australia
Cancer Research Division, The Kinghorn Cancer Centre/Garvan Institute of Medical Research, Sydney, NSW, Australia
La Trobe Institute for Molecular Science, Department of Biochemistry and Genetics, La Trobe University, Melbourne, Victoria, Australia
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia
Departments of Urology and Surgery, Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia
Australian Prostate Cancer Research Centre Epworth, Richmond, Victoria, Australia
Sir Peter MacCallum, Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
Department of Medical Oncology, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia
Department of Urology, Frankston Hospital, Frankston, Victoria, Australia
Central Clinical School, University of Sydney, Camperdown, NSW, Australia
Genomics and Epigenetics Division, Garvan Institute of Medical Research, Sydney, NSW, Australia
Division of Immunology, Garvan Institute of Medical Research, Sydney, NSW, Australia
Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
Freemason's Foundation Centre for Men's Health, University of Adelaide Medical School, Adelaide, SA, Australia
South Australian Health and Medical Research Institute, Adelaide, SA, Australia
Issue Date: 21-Apr-2020
Date: 2020-04-21
Publication information: EMBO reports 2020; 21(6): e50162
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.
DOI: 10.15252/embr.202050162
ORCID: 0000-0002-4909-2984
Journal: EMBO reports
PubMed URL: 32314873
Type: Journal Article
Subjects: bone metastasis
immune evasion
Prostate cancer
type I interferon
Appears in Collections:Journal articles

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