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Investigating the biological response to tumour hypoxia and specifically, the levels of hypoxia most associated with radiation resistance.

The hammond group are working at the interface of the hypoxia induced unfolded protein and DNA damage responses (UPR and DDR respectively). They have recently described the induction of the DNA/RNA helicase Senataxin by the PERK-mediated arm of the UPR in hypoxic conditions (Ramchandran, Ma et al., submitted manuscript). This image highlights that both the UPR and DDR are induced with the same oxygen-dependency in hypoxia conditions (Bolland, Ma et al., Biochem Soc Trans in press 2021)
The Hammond group are working at the interface of the hypoxia induced unfolded protein and DNA damage responses (UPR and DDR respectively). They have recently described the induction of the DNA/RNA helicase Senataxin by the PERK-mediated arm of the UPR in hypoxic conditions (Ramchandran, Ma et al., submitted manuscript). This image highlights that both the UPR and DDR are induced with the same oxygen-dependency in hypoxia conditions (Bolland, Ma et al., Biochem Soc Trans in press 2021)

RESEARCH:

The focus of the Hammond laboratory is the detailed investigation of the biological response to tumour hypoxia and specifically, the levels of hypoxia most associated with radiation resistance and therefore therapy failure. Over the last twenty years, Ester Hammond has provided significant insight into the underlying mechanisms and consequence of the DNA damage response (DDR) in hypoxia and has established herself as a leader in this field. Seminal work includes establishing that replication stress accumulates in response to hypoxia and is responsible for subsequent ATR/ATM signalling (1,2). Most importantly, her work focuses on translating basic science discoveries into strategies to improve radiation response. This is evidenced by studies which underpin the clinical testing of ATR inhibitors with radiotherapy for the treatment of oesophageal cancer (3) in collaboration with Prof. Maria Hawkins. Most relevant to this application is her work focused on the impact of PARP inhibition in hypoxic conditions. In collaboration with Professor Robert Bristow (Manchester University), Ester Hammond was the first to coin the term ‘contextual synthetic lethality’ which refers to the repression of one pathway in response to a physiological stress (hypoxia) leading to increased sensitivity to pharmacological inhibition of a second pathway (PARP inhibitor) (4). Since then and in collaboration with Dr Andy Ryan’s group, she has gone on to demonstrate this phenomenon in combination with radiation in in vivo models of non-small cell lung cancer (5). The research programme, led by Prof Amato Giaccia, will be reliant on the Hammond lab to provide expert assistance in determining the oxygen-dependency of PARP inhibitor sensitivity. Interestingly, recent collaborative work from the Hammond group describes the PARylation of HIF-1 and the requirement for this post translational modification for hypoxia adaption and HIF-recruitment to chromatin (6). In particular, Ester Hammond’s focus on redox balance in hypoxic conditions will be invaluable to the Giaccia lab. Ester Hammond and her long-term collaborator, Professor Stuart Conway (Chemistry, Oxford), were recently awarded an EPSRC programme grant to generate and validate novel redox probes to facilitate the detailed characterisation of the redox environment in physiologically relevant conditions. The use of novel ratiometric probes (currently in development in the Conway lab) to determine changes in specific reactive oxygen species (ROS) will be key to the mechanistic understanding of differences in response to DDR inhibitors (including PARPi and PolQi) in different levels of hypoxia. Furthermore, Hammond and colleagues in Cambridge and the Oxford Maths department have been awarded CRUK funding to investigate the periodicity and magnitude of oxygen fluctuations in tumours. This will allow them to provide physiologically relevant information to the Giaccia lab to ensure that the oxygen levels studied in the lab occur in tumours and, most importantly, how oxygen levels fluctuate. In collaboration with Dr Monica Olcina, Ester Hammond has already described unique NF-kB mediated signalling which occurs in response to cyclic hypoxia but not chronic hypoxia highlighting these distinct biological responses (Bader et al., under review). Fluctuating or cyclic hypoxia is predicted to have significant impact on ROS and therefore links between the CRUK, EPSRC funded projects and OIRO will be impactful. Specifically, the programmes proposed by Drs Moon, D’Angiolella and Petersson will benefit from collaboration with Hammond for example through the use of bespoke tools to assay ROS during ferroptosis; after perturbation of NRF2 signalling or in response to FLASH respectively. Evidence of an existing collaboration between Hammond and Petersson is provided through joint publication and co-supervision of a MRes student (7)

Recent work from the Hammond lab has focused on the discovery that the DNA/RNA helicase, Senataxin (SETX), has roles in hypoxia which include the resolution of transcription-associated R-loops (Ramachandran, Ma et al., BioRxiv, under review). One of the most interesting and novel aspects of this work was the finding that hypoxia mediated SETX expression was controlled by the unfolded protein response (UPR). The linking of R-loops and the UPR is entirely novel and prompted Ester Hammond and Kristijan Ramadan to carry out and publish a systematic review of the literature designed to identify further links between these two areas of biology (Bolland, Ma et al., Biochem Soc Trans in press). Since making the novel discovery that R-loops accumulate in hypoxia, the Hammond lab in collaboration with Dr Tim Humphrey have gone on to provide a mechanism-based description of the accumulation of R-loops at the rDNA in hypoxic conditions (Ng et al., in preparation). Given the complexities of assaying R-loops, the collaboration between the Hammond and Humphrey labs is this area provides significant added value. 

Understanding the chromatin landscape is critical to understanding the hypoxia induced DDR, for example the ATM kinase is activated in hypoxia as a result of both replication stress and increased methylation of histone 3 at lysine 9 (H3K9me3) (1,8). Since these discoveries, Hammond, again in collaboration with Conway, has gone on to develop chromatin modifying tools which could be of use to the wider OIRO group. For example, a hypoxia activated inhibitor of histone deacetylases (9).

Ester Hammond has recently been appointed as the scientific lead for research focused on the tumour microenvironment in the Department of Oncology. As such she provides oversight of this area and plays a key role in the Oxford community and beyond. Finally, Ester Hammond is the Director for the Oxford-MRC DTP which provides comprehensive support for graduate students undertaking medical research. Through her involvement with this programme and as a member of the Medical Sciences Graduate Executive group, Hammond brings valuable knowledge and experience to the OIRO-based training programmes.  

References:

1. ​Olcina MM, Foskolou IP, Anbalagan S, Senra JM, Pires IM, Jiang Y, et al. Replication Stress and Chromatin Context Link ATM Activation to a Role in DNA Replication. Molecular Cell. 2013 Dec;52(5). 

2.  Foskolou IP, Jorgensen C, Leszczynska KB, Olcina MM, Tarhonskaya H, Haisma B, et al. Ribonucleotide Reductase Requires Subunit Switching in Hypoxia to Maintain DNA Replication. Molecular Cell. 2017 Apr;66(2). 

3. Leszczynska KB, Dobrynin G, Leslie RE, Ient J, Boumelha AJ, Senra JM, et al. Preclinical testing of an ATR inhibitor demonstrates improved response to standard therapies for esophageal cancer. Radiotherapy and Oncology. 2016 Nov;121(2). 

4. Chan N, Pires IM, Bencokova Z, Coackley C, Luoto KR, Bhogal N, et al. Contextual Synthetic Lethality of Cancer Cell Kill Based on the Tumor Microenvironment. Cancer Research. 2010 Oct 15;70(20). 

5. Jiang Y, Verbiest T, Devery AM, Bokobza SM, Weber AM, Leszczynska KB, et al. Hypoxia Potentiates the Radiation-Sensitizing Effect of Olaparib in Human Non-Small Cell Lung Cancer Xenografts by Contextual Synthetic Lethality. International Journal of Radiation Oncology*Biology*Physics. 2016 Jun;95(2). 

6. Martí JM, Garcia-Diaz A, Delgado-Bellido D, O’Valle F, González-Flores A, Carlevaris O, et al. Selective modulation by PARP-1 of HIF-1α-recruitment to chromatin during hypoxia is required for tumor adaptation to hypoxic conditions. Redox Biology. 2021 May;41. 

7. Wilson JD, Hammond EM, Higgins GS, Petersson K. Ultra-High Dose Rate (FLASH) Radiotherapy: Silver Bullet or Fool’s Gold? Frontiers in Oncology. 2020 Jan 17;9. 

8. Olcina MM, Leszczynska KB, Senra JM, Isa NF, Harada H, Hammond EM. H3K9me3 facilitates hypoxia-induced p53-dependent apoptosis through repression of APAK. Oncogene. 2016 Feb 11;35(6).

9. Skwarska A, Calder EDD, Sneddon D, Bolland H, Odyniec ML, Mistry IN, et al. Development and pre-clinical testing of a novel hypoxia-activated KDAC inhibitor. Cell Chemical Biology. 2021 Apr;