Biology subjects

Waugh, D.

Publications and source records attributed to Waugh, D..

3 recordsLinked to original sources

bioRxiv2022

IRF7 impacts on prostate cancer cell survival in response to radiation

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 example, irradiation sensitised surviving cells to either a combination of an IKK{varepsilon}/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.

cancer biology↗

bioRxiv2019

Modulating the unfolded protein response: Impacts of radiation on the response of prostate cancer cells to ONC201

Prostate cancer (PCa) is the most common non-cutaneous cancer in men and a notable cause of cancer mortality when it metastasises. Localised disease is mostly treated with surgery or radiotherapy. As PCa develops and treatment resistance emerges, the unfolded protein response (UPR) arises as an important adaptive biology co-amplifying with key cancer drivers [1]. The UPR can be cytoprotective but when acutely activated can lead to cell death. In this study we sought to enhance the acute activation of the UPR using radiation and ONC201, previously reported to be an UPR activator [2]. We found that treating PCa cells with ONC201 quickly increases the expression of components in all arms of the UPR - ATF4, ATF6 and IRE1-XBP1 - culminating in the subsequent cell death. During this time window between UPR activation and cell death we tested the priming effect of short-term administration of ONC201 on radiation responses. Pre-treatment with ONC201 for 24 hours prior to irradiation led to enhanced cytotoxicity compared to radiation alone assessed by cell viability and clonogenic assays. With priming, RNA-Seq analysis showed a sustained suppression of transcripts encoding cell cycle regulators as well as components of the DNA damage response pathways. Phenotypically this was reflected in enhanced cell cycle arrest and induction of necrosis and apoptosis. Furthermore, we demonstrated that short-term administration of inhibitors of cell cycle regulators (Dinaciclib and BI2536), could replicate this priming effect. Thus, we propose future studies to assess the impact of the short-term administration of drugs targeting the UPR and cell cycle regulation to enhance radiotherapy response.

cancer biology↗

bioRxiv2019

Trait plasticity of intensive pasture species due to growth in mixture across seasons and nutrient addition levels

QuestionsHow do the traits of pastoral species respond to growth in mixture, nitrogen addition and season? What are the impacts of trait plasticity on community aggregate trait values?\n\nStudy siteA large-scale field experiment on intensively managed dairy pastures in New Zealand.\n\nMethodsWe measured traits linked to rate of return on investment in leaves - leaf nitrogen content (leaf N) and specific leaf area (SLA) - and biomass investment in leaf area - leaf area ratio (LAR). We collected trait data for 5 pasture species (one grass, two forbs, and two N2-fixing legumes) grown in monoculture or a five-species mixture across three levels of nitrogen (N) addition in four seasons. For each species in each season we tested for significant effects of growth in mixture, N addition, and their interaction. We calculated community-weighted mean (CWM) values in mixture plots using traits collected either from mixtures or monocultures. We tested for significant mixture and N addition effects on CWM, and for significant interactions between mixture and N addition.\n\nResultsSLA and LAR for all non-N2-fixers were significantly higher in spring, summer or autumn, and never significantly lower in mixture than in monoculture. All three non-N2-fixers experienced higher leaf N in mixture during summer, but two species had significantly lower leaf N in either winter or autumn. Mixture effects on CWM values for all three traits were negative in winter and positive in either spring or summer.\n\nConclusionsThe direction of trait plasticity effects on community level trait means was highly seasonally dependent.

ecology↗