Solar UV irradiation of the skin causes DNA damage, which if not repaired correctly, can result in mutations. Consistently, cutaneous melanoma frequently has a high mutational burden, making it more aggressive and difficult to treat. However, it is not known whether these cells have specific pro-survival mechanisms or enhanced DNA repair capacity. The transcription factor BRN2 is a known driver of invasiveness and regulator of proliferation in melanoma. In this article published in Genes and Development, Katie Herbert and colleagues from Colin Goding’s lab show that BRN2 associates with sites of DNA damage and promotes a more error-prone DNA repair mechanism. Furthermore, BRN2 also reduces cell death of damaged cells. This work has implications for the treatment of melanoma using DNA-damaging agents in cancers expressing BRN2.
DNA methylation has been well studied and is known to influence development and disease. In contrast, the dearth of suitable RNA methylation sequencing methods has meant that much less is known about these modifications. In this paper published in Chemical Communications, Ludwig Oxford’s Fang Yuan and Ying Bi from Chunxiao Song’s group develop a base-resolution sequencing method for 5-methylcytidine and 5-hydroxymethylcytidine based on a peroxotungstate oxidation reaction. This method will enable important further characterisation of these modifications.
Methylation and hydroxymethylation of cytosine (5mC and 5hmC) are chemical epigenetic modifications of DNA that are associated with changes in gene expression. Up until now, the main method for detecting these modifications relied on harsh bisulphite treatment, making it challenging to measure levels in samples with low amounts of DNA. In this paper published in Nature Biotechnology, Ludwig Oxford researchers from Chunxiao Song’s and Benjamin Schuster-Böckler’s groups develop TAPS (TET-assisted pyridine borane sequencing), a novel bisulphite-free, base resolution and highly sensitive method for measuring 5mC and 5hmC, in addition to detecting DNA mutations and copy number variations. Since levels of 5mC and 5hmC change in cancer, detection of methylation on circulating tumour DNA within blood samples could form the basis of a blood-based cancer test. For more information, see the Ludwig Cancer Research press release and the Nature Biotechnology "Behind the Paper" blog.
The interactions between cells and their relative motions are important for the correct maintenance of tissues, and alterations can cause disease. However, there are limited existing tools that can measure these motion phenotypes. Published in eLife, Ludwig Oxford’s Felix Zhou and Carlos Ruiz-Puig from Xin Lu’s and Jens Rittscher’s labs have developed a new computational framework, Motion Sensing Superpixels (MOSES), which can quantify and characterise cellular dynamics. This tool will improve the analysis of biological motion, for example in high-throughput imaging screens, to accelerate our understanding of this important area of biology.
Unfortunately, only 15% patients diagnosed with oesophageal cancer survive 5 years. Part of the reason for the high mortality is the frequently late detection of this cancer, making current treatments less effective. At Ludwig Oxford, we are researching both new early detection methods and new treatment combinations to improve the outcomes of patients with this disease. The CRUK Oxford Centre have highlighted our research in their recent blogs ...
People with red hair carry variants of the MC1R gene, which puts them at increased risk of developing melanoma. A proposed risk reduction strategy is to increase the level of a modification called palmitoylation on the MC1R protein, which would beneficially increase MC1R activity. However, the mechanism to enable this strategy had not yet been discovered. In this Nature Communications article, Ludwig Oxford’s Colin Goding and co-workers from Boston University School of Medicine and Shandong Normal University, China, identify the enzyme APT2 responsible for removing MC1R palmitoylation and show that APT2 inhibition rescues defects in variant MC1R activity. APT2 inhibition could therefore form the basis for a new preventative/therapeutic strategy for reducing melanoma risk in redheads and others.
Autophagy is the process by which the cell recycles damaged or unwanted components. Recently, repression of autophagy has become an attractive anti-cancer therapeutic strategy, however, there are reports that autophagy inhibition may also promote tumour invasion and metastasis. To investigate these concerns, Ludwig Oxford’s Yihua Wang from Xin Lu’s lab studied the effect of autophagy inhibition on the epithelial to mesenchymal transition (EMT), a key step in tumour metastasis. Their results, published in Autophagy, show that autophagy inhibition promotes the EMT in tumours whose growth is driven by mutation of the Ras family of growth-promoting proteins but not in tumours with normal Ras. This work has implications on how these new therapies are used to treat RAS-mutated cancer.
Arteries and veins have different types of endothelium but it is unclear how these molecular and functional differences are specified during development. To understand more, Ludwig Oxford’s Alice Neal and colleagues from Sarah De Val’s group studied venous development in mice and zebrafish. They found that BMP signalling is required for transcriptional activation of the key venous regulator Ephb4 and subsequent establishment of venous blood vessels. This work, published in Nature Communications, therefore identifies a new potential target for anti-angiogenic therapy to reduce tumour growth.
The Journal of Cell Science has interviewed former Ludwig Oxford PhD student Norbert Volkmar as part of their “First Person” features. Norbert, a former graduate student from John Christianson’s lab, recently published his PhD research on the ER membrane protein complex in the journal. Norbert and other members of the Christianson group discovered that this complex is required for the correct synthesis of two important proteins that control the levels of cholesterol in the cell.
Cancer metastasis is the primary cause of cancer-related death but it is unclear why cancer cells migrate away from the original tumour site. In this review in Cell Metabolism, Ludwig Oxford’s Colin Goding and Custodia García-Jimenéz (Madrid) propose that invasive behaviour in cancer is caused either by nutrient or oxygen limitation within the tumour, or by signals from immune cells or therapy that hijack the cell’s starvation response to impose a pseudo-starvation state. By explaining how many apparently unrelated triggers for invasion converge on a single cell survival strategy, similar from bacteria to man, the authors identify a therapeutic vulnerability in invasive cancer cells.