Prostate cancer cell‐intrinsic interferon signaling regulates dormancy and metastatic outgrowth in bone
| Autor: | Alex Spurling, John M. Mariadason, Lisa M. Butler, Linden J. Gearing, Niall M. Corcoran, Stefano Mangiola, Katie L. Owen, Peter I. Croucher, Natasha K Brockwell, Daniel L. Roden, Alexander Swarbrick, Ruth J. Lyons, Weng Hua Khoo, Matthew K.H. Hong, Anupama Pasam, Chia Ling Chan, Andrew Ryan, Michelle M. McDonald, Vanessa M. Hayes, Hendrika M. Duivenvoorden, Tri Giang Phan, Damien Zanker, Paul J. Hertzog, Shahneen Sandhu, Christopher M. Hovens, Marek Cmero, Belinda S. Parker |
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| Rok vydání: | 2021 |
| Předmět: |
Male
dormancy Immunology Bone Neoplasms Biochemistry Article 03 medical and health sciences Prostate cancer 0302 clinical medicine Immune system Interferon Bone cell Genetics medicine Humans Molecular Biology bone metastasis immune evasion Cancer 030304 developmental biology Uncategorized 0303 health sciences business.industry Immunogenicity Prostatic Neoplasms Bone metastasis Articles prostate cancer medicine.disease Cancer cell Cancer research type I interferon Interferons Signal transduction business 030217 neurology & neurosurgery Signal Transduction medicine.drug |
| Zdroj: | EMBO Reports |
| DOI: | 10.26181/5ff3aa461badd |
| Popis: | 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. Tumor‐intrinsic type I IFN is lost upon outgrowth of dormant prostate cancer cells in bone, driving metastasis. Therapeutic reversal of tumor‐intrinsic IFN loss enhances tumor cell visibility and the effectiveness of systemic immunomodulatory agents against bone‐metastasis. |
| Databáze: | OpenAIRE |
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