Translational Biology
We are investigating the mechanisms by which cancer mutations deregulate the normal processes of cellular function and growth. We use genome-wide profiling to screen different classes of cancer, such as colorectal cancer, for potential mutations and biomarkers. We study how cancer evolves, and are developing better molecular and cellular cancer models for designing and testing new therapies.
For example, Professor Andrew Beggs’ research is looking at devising organoid models to offer personalised medicine treatments for colorectal cancer patients, and Professor Richard Bryan is developing a 23-gene panel for a non-invasive diagnosis for . In 2022 Andrew Beggs was awarded a £1.5 million MRC Senior Clinical Fellowship to continue using organoid models to study mechanisms of treatment resistance in colorectal cancer.
Theme Lead and Deputy Theme Lead
Dr Claire Palles
Associate Professor / Theme Lead
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Dr Gianmarco Contino
Associate Professor of Cancer Genomic Medicine / Deputy Theme Lead
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Research Groups
Spotlight on neuronal cell death linked to NAD depletion during loss of autophagy
Researchers at the University 麻豆精选 have shown that autophagy is essential for maintaining normal NAD levels and mitochondrial function. Loss of autophagy genes results in depletion of NAD, leading to mitochondrial depolarisation and cell death in neurons.
Cell Reports 42:112372 (2023). Sun C, E Seranova, MA Cohen, M Chipara, J Roberts, D Astuti, . . . VI Korolchuk and S Sarkar.
Developmental Cell 57:2584-2598 e2511 (2022). Kataura T, L Sedlackova, EG Otten, R Kumari, D Shapira, F Scialo, R Stefanatos, K Ishikawa, G Kelly, E Seranova, C Sun . . . . . .S Sarkar and VI Korolchuk.
Autophagy is a cellular catabolic process that mediates recycling of undesirable intracellular components such as aggregated proteins and damaged organelles like mitochondria to maintain proper homeostasis of cells and is also needed to preserve energy levels within cells. Two joint studies by Sovan Sarkar at the University 麻豆精选 and Viktor Korolchuk at Newcastle University have now shown an essential role of autophagy in ensuring cell survival by preserving the levels of nicotinamide adenine dinucleotide (NAD). Enzymes that consume NAD, such as PARP and Sirtuins, are hyperactive in autophagy-deficient cells, leading to cellular depletion of NAD. Loss of autophagy by knockout of essential autophagy gene ATG5 results in NAD exhaustion, leading to mitochondrial membrane depolarisation and cell death in human embryonic stem cells and in human neurons. This cytotoxic cascade is shown to be evolutionarily conserved from yeast to humans. These findings help explain the basis of neurodegeneration and lysosomal storage disorders linked to autophagic defects. This story was also the subject of a UoB press release.
Spotlight on Drugs that promote spinal cord repair after injury
Science Advances 8 (2022) eabq2611.Taylor MJ, Thompson AM, Alhajlah S, Tuxworth RI, Ahmed Z. .
Clinical and Translational Medicine 12 (2022) e962. Ahmed Z, Tuxworth RI. .
Ground-breaking recent studies from the Ahmed and Tuxworth laboratories have shown that 2 drugs designed to cure cancer can now potentially be used to promote spinal cord and optic nerve repair after injury. Anti-cancer drugs that target either ATM or CHK2 in the DNA repair pathway promote the survival of neurons and the re-growth of axons across sites of nerve damage. DNA double strand breaks in damaged neurons normally trigger a DNA damage response that blocks regrowth of axons and often results in cell death. Remarkably, inhibition of the ATM/CHK2 pathway led to a return of normal transmission of nerve impulses across damaged spinal cords or optic nerves in models of injury in animals where electrical transmission across damaged neurons had been blocked. When these drugs were given within 24 hours of spinal cord injury in animal models, they promoted full recovery of hind limb function and sensation within a few weeks. These drugs are already in development or in use for cancer and may in the future be investigated for their potential use to promote recovery from spinal cord injury in people.
Spotlight on the Regulation of Carcinogenesis in Colorectal Cancer
Proc Natl Acad Sci U S A 118 (2021) e2011411118. Andrijes R, RK Hejmadi, M Pugh, S Rajesh, V Novitskaya, M Ibrahim, ….. A Beggs, F Berditchevski. Tetraspanin 6 is a regulator of carcinogenesis in colorectal cancer. doi: 10.1073/pnas.2011411118
Bowel cancer patients expressing high levels of the membrane-bound protein TPSPAN6 are more likely to respond to treatment with Cetuximab, a monoclonal antibody inhibitor of the EGF receptor. Previously it has been difficult to identify bowel cancer patients likely to benefit from Cetuximab because only some of these patients respond to therapy, partly due to the fact a subset of these patients have KRAS mutations, and these patients may not even be eligible for Cetuximab. This study in PNAS from the groups of Fedor Berditchevski and Andrew Beggs reveals that TSPAN6 is a tumour suppressor that blocks the autocrine expression of membrane bound TGFa on vesicles that activate EGFR signalling. High levels of TSPAN6 expression are associated with enhanced sensitivity to Cetuximab, regardless of the KRAS mutation status. These finding may pave the way for personalised therapy in bowel cancer whereby TSPAN6 can be used as a biomarker to target patients most likely to benefit from Cetuximab, including those with KRAS mutations.
Spotlight on COVID-19 and Cancer Patients
Cancer Cell 38:306-307 (2020). Lee LYW, T Hill, O Topping, M Tilby, M Baker, J Greig, . . . UKBCCC- Project. .
Cancer patients are at increased risk from COVID-19. In this study led by Lennard Lee COVID-19 tests were performed in 1,226 patients as part of the UK Birmingham Chemotherapy Cancer COVID-19 cohort. Uptake of screening was 98.2%, with an asymptomatic infection prevalence of 0.6%. This study concluded that where the incidence of asymptomatic infection is low and patients can be identified early, screening gives clinicians the confidence to safely deliver effective cancer care in the era of COVID-19.
Selected Highlights from this research theme
Cell Reports 42:112372 (2023). Sun C, E Seranova, MA Cohen, M Chipara, J Roberts, D Astuti, . . . VI Korolchuk and S Sarkar.
18:1090-1106 (2023). Zatyka M, TR Rosenstock, C Sun, AM Palhegyi, GW Hughes, S Lara-Reyna, . . . T Barret and S Sarkar. Depletion of WFS1 compromises mitochondrial function in hiPSC-derived neuronal models of Wolfram syndrome.
Eur Urol Oncol 6:67-75 (2023). Ward DG, L Baxter, S Ott, NS Gordon, J Wang, P Patel, . . . R Bryan, BladderPath Trial Management Group. Highly Sensitive and Specific Detection of Bladder Cancer via Targeted Ultra-deep Sequencing of Urinary DNA.
Cell Reports 42:112207 (2023). Molostvov G, M Gachechiladze, AM Shaaban, S Hayward, I Dean, IHK Dias, . . . F Berditchevski. .
Developmental Cell 57:2584-2598 e2511 (2022). Kataura T, L Sedlackova, EG Otten, R Kumari, D Shapira, F Scialo, . . .S Sarkar and VI Korolchuk. .
Pediatr Radiol 52:1134-1149 (2022). Withey SB, L MacPherson, A Oates, S Powell, J Novak, L Abernethy, . . . AC Peet. .
Sci Adv 8:eabq2611 (2022). Taylor MJ, AM Thompson, S Alhajlah, RI Tuxworth and Z Ahmed. I.
Clin Transl Med 12:e962 (2022). Ahmed Z and RI Tuxworth.
Eur Urol Oncol Online: DOI: 10.1016/j.euo.2022.03.005 (2022). Ward DG, L Baxter, S Ott, NS Gordon, J Wang, P Patel, . . . R Bryan, G BladderPath Trial Management Group. .
Am J Hum Genet 109:953-960 (2022). Palles C, HD West, E Chew, S Galavotti, C Flensburg, JE Grolleman, . . . RM de Voer. .
Genome Med 14:59 (2022). Goel A, DG Ward, B Noyvert, M Yu, NS Gordon, B Abbotts, . . . RT Bryan. .
Gut Online: doi: 10.1136/gutjnl-2021-326698 (2022). Schroder J, L Chegwidden, C Maj, J Gehlen, J Speller, AC Bohmer, . . . C Palles, J Schumacher. .
Eur Urol 80:12-15 (2021). Bryan RT, W Liu, SJ Pirrie, R Amir, J Gallagher, AI Hughes, . . . P Patel, ND James. .
Cancers (Basel) 13:2779 (2021). Dragomir I, A Akbar, JW Cassidy, N Patel, HW Clifford and G Contino. I.
Clin Microbiol Infect 27:1348 e1341-1348 e1347 (2021). Ptasinska A, C Whalley, A Bosworth, C Poxon, C Bryer, N Machin, . . . AD Beggs. .
Epigenomes 5:6 (2021). Whalley C, K Payne, E Domingo, A Blake, S Richman, J Brooks, . . . AD Beggs.
PNAS (Proceedings of the National Academy of Sciences of the United States of America) 118 (39) e2011411118 (2021) Regina Andrijes, Rahul K. Hejmadi, Matthew Pugh, Sundaresan Rajesh, Vera Novitskaya, Maha Ibrahim, Michael Overduin, Chris Tselepis, Gary W. Middleton, Balázs Győrffy, Andrew D. Beggs, and Fedor Berditchevski .
Cancers (Basel) 13:1497(2021). Palles C, S Fotheringham, L Chegwidden, M Lucas, R Kerr, G Mozolowski, . . . D Kerr. .
Cancer Research 81:1667-1680 (2021). Zhang P, I Kitchen-Smith, L Xiong, G Stracquadanio, K Brown, PH Richter, . . . GL Bond. .
J Medical Genetics 58: 392-299 (2020). Di Giovannantonio M, BH Harris, P Zhang, I Kitchen-Smith, L Xiong, N Sahgal, . . . GL Bond. .
British J Cancer 122:1231-1241 (2020). Surakhy M, M Wallace, E Bond, LF Grochola, H Perez, M Di Giovannantonio, . . . GL Bond. .
Cancers (Basel) 12:1278 (2020). Wanigasooriya K, R Tyler, JD Barros-Silva, Y Sinha, T Ismail and AD Beggs. .
Lancet 395:1268-1277 (2020). Birtle A, M Johnson, J Chester, R Jones, D Dolling, RT Bryan, . . . E Hall. .
Clin Oncol (R Coll Radiol) 10:1016 (2020). Best J, T Starkey, A Chatterjee, D Fackrell, L Pettit, N Srihari, . . . JB Cazier, LYW Lee. .
J Clin Virol 128:104469 (2020). Bosworth A, C Whalley, C Poxon, K Wanigasooriya, O Pickles, EL Aldera, . . . AD Beggs. .
Lancet Oncol 21:1309-1316 (2020). Lee LYW, JB Cazier, T Starkey, SEW Briggs, R Arnold, V Bisht, . . . UKCCMP Team. .
J Mol Biol 432:2754-2798 (2020). Seranova E, AM Palhegyi, S Verma, S Dimova, R Lasry, M Naama, . . . S Sarkar. .
Cancer Cell 38:306-307 (2020). Lee LYW, T Hill, O Topping, M Tilby, M Baker, J Greig, . . . UKBCCC- Project.
J Mol Biol 432:2735-2753 (2020). Zatyka M, S Sarkar and T Barrett. .
Brain Commun 1:fcz005 (2019). Tuxworth RI, MJ Taylor, A Martin Anduaga, A Hussien-Ali, S Chatzimatthaiou, J Longland, . . . Z Ahmed. Attenuating the DNA damage response to double-strand breaks restores function in models of CNS neurodegeneration.
Sci Rep 9:15592 (2019). Connolly KJ, MB O'Hare, A Mohammed, KM Aitchison, NC Anthoney, MJ Taylor, . . . RI Tuxworth, G Tear. .
N Engl J Med 381:637-646 (2019). Tamborlane WV, M Barrientos-Perez, U Fainberg, H Frimer-Larsen, M Hafez, PM Hale, . . . T Barrett, Ellipse Trial. .
Cancer Cell 30:578-594 (2016). Bardella C, O Al-Dalahmah, D Krell, P Brazauskas, K Al-Qahtani, M Tomkova, . . . I Tomlinson. .
Mol Cell 53:645-654 (2014). Feng T, A Yamamoto, SE Wilkins, E Sokolova, LA Yates, M Munzel, . . . ML Coleman. .
Oncogene 32:5333-5337 (2013). Beggs AD, E Domingo, M Abulafi, SV Hodgson and IP Tomlinson. .
Nat Genet 45:136-144 (2013). Palles C, JB Cazier, KM Howarth, E Domingo, AM Jones, P Broderick, . . . I Tomlinson. .
Cell Rep 5:1302-1315 (2013). Sarkar S, B Carroll, Y Buganim, D Maetzel, AH Ng, JP Cassady, . . . R Jaenisch. .