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Prostate cancer cell‐intrinsic interferon signaling regulates dormancy and metastatic outgrowth in bone
journal contributionposted on 04.01.2021, 23:52 by Katie L Owen, LJ Gearing, Damien J Zanker, Natasha Brockwell, WH Khoo, DL Roden, M Cmero, S Mangiola, MK Hong, Alex J Spurling, M McDonald, CL Chan, A Pasam, RJ Lyons, Hendrika M Duivenvoorden, A Ryan, LM Butler, John Mariadason, T Giang Phan, VM Hayes, S Sandhu, A Swarbrick, NM Corcoran, PJ Hertzog, PI Croucher, C Hovens, Belinda Parker
© 2020 Peter MacCallum Cancer Centre. Published under the terms of the CC BY NC ND 4.0 license 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.
The authors thank the patients who donated material for this study and the efforts of all Biobank staff. This project is supportesd by grant funding from the Prostate Cancer Foundation of Australia and Movember (Movember Revolutionary Team Award) to P.I.C., B.S.P., C.H., N.C., A.S., and V.M.H., and Fellowship funding to B.S.P. (Australian Research Council Future Fellowship, FT130100671; Victorian Cancer Agency Mid-career fellowship, MCRF16022).
Rights StatementThe Author reserves all moral rights over the deposited text and must be credited if any re-use occurs. Documents deposited in OPAL are the Open Access versions of outputs published elsewhere. Changes resulting from the publishing process may therefore not be reflected in this document. The final published version may be obtained via the publisher’s DOI. Please note that additional copyright and access restrictions may apply to the published version.
Science & TechnologyLife Sciences & BiomedicineBiochemistry & Molecular BiologyCell Biologybone metastasisdormancyimmune evasionprostate cancertype I interferonDISSEMINATED TUMOR-CELLSSUPPRESSOR-CELLSGENE-EXPRESSIONRAPID AUTOPSYLONG-TERMIMMUNEMECHANISMSRECEPTORSURVIVALACTIVATIONDevelopmental Biology