ORCID Profile
0000-0002-4850-4086
Current Organisations
University of Helsinki
,
University of Oxford
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Publisher: Cold Spring Harbor Laboratory
Date: 23-09-2022
DOI: 10.1101/2022.09.23.509205
Abstract: Understanding the impact of radiotherapy on the evolution of treatment resistant prostate cancer is critical for selecting effective treatment combinations. Whilst activation of Type 1 interferon signalling is a hallmark of how cells respond to viral infection, in cancer cells, multiple stresses are known to activate this same response. In this study we have evaluated for the first time the changes in the interferon response induced by culturing prostate cancer cells under sphere- forming conditions and following irradiation. We report a conserved upregulated transcript profile for both conditions that is strongly associated with therapeutic resistance and cell survival in vitro and in vivo. The profile includes and is regulated by the Type 1 interferon master regulator IRF7 which, when depleted, delays tumour re-growth following irradiation. We immuno-stained two independent prostate cohorts for IRF7 and found that increased expression, particularly in cases with low PTEN expression, correlated with poor prognosis. To more comprehensively characterise the impact of IRF7 and radiation on cells, RNA-Seq was performed on IRF7 knockdown cells at different radiation doses. We identified a number of biological processes that were IRF7-dependent, including the formation of stem-like cell populations and also therapeutic vulnerabilities. For ex le, irradiation sensitised surviving cells to either a combination of an IKKε/TBK1 and a MEK inhibitor or treatment with an inhibitor of IDO1, an IRF7- dependent gene. Translationally our work suggests that IRF7 expression can be used to stratify patients who may not benefit from receiving radiotherapy alone but rather may benefit from treatment combinations. In two cohorts treated with radical intent, strong IRF7 staining was associated with disease-specific death implicating this pathway as a convergence point for therapeutic resistance in prostate and potentially other cancer types.
Publisher: Wiley
Date: 2021
DOI: 10.1002/BCO2.60
Publisher: Cold Spring Harbor Laboratory
Date: 04-06-2021
DOI: 10.1101/2021.06.03.21256653
Abstract: The need to better understand the molecular underpinnings of the heterogeneous outcomes of patients with prostate cancer is a pressing global problem and a key research priority for Movember. To address this, the Movember Global Action Plan 1 Unique tissue microarray (GAP1-UTMA) project constructed a set of unique and richly annotated TMAs from prostate cancer s les obtained from multiple institutions across several global locations. Three separate TMA sets were built that differ by purpose and disease state. The intended use of TMA1 is to validate biomarkers that help determine which clinically localized prostate cancers with associated lymph node metastasis have a high risk of progression to lethal castration resistant metastatic disease, and to compare molecular properties of high risk index lesions within the prostate to regional lymph node metastases resected at the time of prostatectomy. TMA2 was designed to address questions regarding risk of castration resistant prostate cancer (CRPC) and response to suppression of the androgen receptor/androgen axis, and characterization of the castration-resistant phenotype. TMA3’s intended use is to assess and better understand the heterogeneity of molecular markers across different anatomic sites in lethal prostate cancer metastases. The GAP1-UTMA project has succeeded in combining a large set of rare tissue specimens from 501 prostate cancer patients with rich clinical annotation. This resource is now available to the prostate cancer community as a tool for biomarker validation to address important unanswered clinical questions around disease progression and response to treatment.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Andrew Erickson.