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Cancer & RNA biology

We are interested in understanding the regulation of RNA and how this is important in normal development and cancer. It is now appreciated that RNA is actively regulated at many levels and this is important for the function both normal cells and in cancer.

Research Overview

We are interested in how RNA editing by ADAR proteins changes the RNA landscape and contributes to normal physiology and cancer. We are also interested in why RNA splicing mutations are so important in the formation of blood cancers, in particular myelodysplastic syndrome. We use the models we generate to identify and develop new therapies for cancer. In a separate theme, we have established faithful small animal models of osteosarcoma, a bone cancer that occurs predominantly in teenagers, and are using this model to determine processes involved in the initiation, progression and metastasis of this cancer.

Honours and PhD Projects

If you are interested in our work and are seeking Honours or PhD opportunities please contact Carl Walkley on [email protected] to enquire about available projects.

Research Themes

RNA editing by ADAR proteins

ADAR proteins catalyse the conversion of adenosine bases in RNA to inosine (termed A-to-I editing). We have used mouse genetics to define the role of Adar1 in vivo, demonstrating that the editing of RNA by ADAR1 is essential to prevent activation of the innate immune sensing system by endogenous RNA. We are continuing to study the role of A-to-I editing in both normal physiology and disease.

Myelodysplastic syndrome and RNA splicing

Myelodysplastic syndrome (MDS) and myelodysplastic/myeloproliferative syndromes (MDS/MPN) are a group of haematological cancers which are predominantly diseases of aging. The only curative treatment, bone marrow transplantation, is unavailable to most patients due to unacceptably high treatment-related mortality in the elderly. Whilst a catalogue of mutations in these cancers is established, how these mutations contribute to disease initiation, maintenance and ultimate evolution is much less clear. We have developed a humanized model of a common mutation found the RNA splicing machinery and are using this to understand how this mutations causes MDS and MDS/MPN.

Osteosarcoma

Osteosarcoma is the most common tumour of bone. We have developed and characterized a unique model of this tumour based on our understanding of the human disease. This model closely mirrors the human disease in terms of histology, transcriptional profile, cytogenetics and metastatic dissemination. We are using this faithful model of human osteosarcoma to further understand the genetics of this disease as well as a pre-clinical model to explore new therapeutic approaches to treat both primary and metastatic disease.

Student Projects

Staff

Publication Highlights

  1. Ng AJ, Walia MK, Smeets MF, Mutsaers AJ, Sims NA, Purton LE, Walsh NC, Martin TJ, Walkley CR. The DNA Helicase Recql4 Is Required for Normal Osteoblast Expansion and Osteosarcoma Formation. PLoS Genetics. 2015 Apr 10;11(4):e1005160.
  2. Gupte A, Baker EK, Wan SS, Stewart E, Loh A, Shelat AA, Gould CM, Chalk AM, Taylor S, Lackovic K, Karlström Å, Mutsaers AJ, Desai J, Madhamshettiwar PB, Zannettino ACW, Burns C, Huang DCS, Dyer MA, Simpson KJ, Walkley CR. Systematic screening identifies dual PI3K and mTOR inhibition as a conserved therapeutic vulnerability in osteosarcoma. Clinical Cancer Research 2015 July 15,21:3216-3229.
  3. Liddicoat BJ, Piskol R, Chalk AM, Ramaswami G, Higuchi M, Hartner JC, Li JB, Seeburg PH, Walkley CR. RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as non-self. Science 2015 Sep 4;349(6252):1115-20.
  4. Heraud-Farlow JE, Chalk AM, Linder SE, Li Q, Taylor S, White JM, Pang L, Liddicoat BJ, Gupte A, Li JB, Walkley CR. Protein recoding by ADAR1-mediated RNA editing is not essential for normal development and homeostasis. Genome Biology (2017) Sep 5;18(1):166.
  5. Walkley CR & Li JB. Rewriting the transcriptome: Adenosine-to-Inosine RNA editing by ADARs. Genome Biology (2017) Oct 30;18(1):205. 
  6. Smeets MF, Tan SY, Xu JJ, Anande G, Unnikrishnan A, Chalk AM, Taylor SR, Pimanda JE, Wall M, Purton LE, Walkley CR. Srsf2P95H initiates myeloid bias and myelodysplastic/myeloproliferative syndrome (MDS/MPN) from hemopoietic stem cells. Blood 2018 Aug 9;132(6):608-621.
  7. Castillo-Tandazo W, Smeets M, Murphy V, Liu R, Hodson C, Heierhorst J, Deans AJ, Walkley CR. ATP-dependent helicase activity is dispensable for the physiological functions of Recql4. PLoS Genetics 2019 Jul 5;15(7):e1008266.
  8. Chalk AC, Taylor S, Heraud-Farlow JE, Walkley CR. The majority of A-to-I RNA editing is not required for mammalian homeostasis. Genome Biology 2019 20:268.
  9. Walkley CR, Kile BT. Cell death following the loss of ADAR1 mediated A-to-I RNA editing is not effected by the intrinsic apoptosis pathway. Cell Death & Disease 2019 10:913.
  10. Castillo-Tandazo W, Frazier AE, Sims NA, Smeets MF, Walkley CR. Rothmund Thompson Syndrome-like RECQL4 truncating mutations cause a haploinsufficient low bone mass phenotype but do not initiate tumorigenesis in mice. Mol Cell Biol 2020 Dec 23: MCB.00590-20. doi: 10.1128/MCB.00590-20.
    For full publication list see ORCID (Carl Walkley: https://orcid.org/0000-0002-4784-9031).

For full publication list see:
ORCID (Carl Walkley: https://orcid.org/0000-0002-4784-9031)