Prostate Cancer Cell-intrinsic Interferon Signaling Regulates Dormancy and Metastatic Outgrowth in Bone

Overview

Journal EMBO Rep

Specialty Molecular Biology

Date 2020 Apr 22

PMID 32314873

Citations 49

Authors

Katie L Owen

Linden J Gearing

Damien J Zanker

Natasha K Brockwell

Weng Hua Khoo

Daniel L Roden

Marek Cmero

Stefano Mangiola

Matthew K Hong

Alex J Spurling

Michelle McDonald

Chia-Ling Chan

Anupama Pasam

Ruth J Lyons

Hendrika M Duivenvoorden

Andrew Ryan

Lisa M Butler

John M Mariadason

Tri Giang Phan

Vanessa M Hayes

Shahneen Sandhu

Alexander Swarbrick

Niall M Corcoran

Paul J Hertzog

Peter I Croucher

Chris Hovens

Belinda S Parker

Affiliations

Soon will be listed here.

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.

Citing Articles

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