Microbiology & Immunology - Research Publications

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Author: Corcoran, Niall × End date: 2022 × Start date: 2020 × Type: Journal Article ×

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    Prostate cancer cell-intrinsic interferon signaling regulates dormancy and metastatic outgrowth in bone
    Owen, KL ; Gearing, LJ ; Zanker, DJ ; Brockwell, NK ; Khoo, WH ; Roden, DL ; Cmero, M ; Mangiola, S ; Hong, MK ; Spurling, AJ ; McDonald, M ; Chan, C-L ; Pasam, A ; Lyons, RJ ; Duivenvoorden, HM ; Ryan, A ; Butler, LM ; Mariadason, JM ; Phan, TG ; Hayes, VM ; Sandhu, S ; Swarbrick, A ; Corcoran, NM ; Hertzog, PJ ; Croucher, P ; Hovens, C ; Parker, BS (WILEY, 2020-06-04)
    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.
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    Detection of ctDNA in plasma of patients with clinically localised prostate cancer is associated with rapid disease progression
    Lau, E ; McCoy, P ; Reeves, F ; Chow, K ; Clarkson, M ; Kwan, EM ; Packwood, K ; Northen, H ; He, M ; Kingsbury, Z ; Mangiola, S ; Kerger, M ; Furrer, MA ; Crowe, H ; Costello, AJ ; McBride, DJ ; Ross, MT ; Pope, B ; Hovens, CM ; Corcoran, NM (BMC, 2020-08-17)
    BACKGROUND: DNA originating from degenerate tumour cells can be detected in the circulation in many tumour types, where it can be used as a marker of disease burden as well as to monitor treatment response. Although circulating tumour DNA (ctDNA) measurement has prognostic/predictive value in metastatic prostate cancer, its utility in localised disease is unknown. METHODS: We performed whole-genome sequencing of tumour-normal pairs in eight patients with clinically localised disease undergoing prostatectomy, identifying high confidence genomic aberrations. A bespoke DNA capture and amplification panel against the highest prevalence, highest confidence aberrations for each individual was designed and used to interrogate ctDNA isolated from plasma prospectively obtained pre- and post- (24 h and 6 weeks) surgery. In a separate cohort (n = 189), we identified the presence of ctDNA TP53 mutations in preoperative plasma in a retrospective cohort and determined its association with biochemical- and metastasis-free survival. RESULTS: Tumour variants in ctDNA were positively identified pre-treatment in two of eight patients, which in both cases remained detectable postoperatively. Patients with tumour variants in ctDNA had extremely rapid disease recurrence and progression compared to those where variants could not be detected. In terms of aberrations targeted, single nucleotide and structural variants outperformed indels and copy number aberrations. Detection of ctDNA TP53 mutations was associated with a significantly shorter metastasis-free survival (6.2 vs. 9.5 years (HR 2.4; 95% CIs 1.2-4.8, p = 0.014). CONCLUSIONS: CtDNA is uncommonly detected in localised prostate cancer, but its presence portends more rapidly progressive disease.