Molecular Signalling Laboratory
The Molecular Signalling Laboratory examines the regulation of cell signalling pathways by sphingolipids; to both determine how defects in this contribute to cancer, wound healing, fibrosis, and other conditions, and to develop agents to target these pathways to improve human health. Primarily our work is concerned with the role of the sphingolipid pathway in cancer, since efects in sphingolipid metabolism can trigger increased cell survival, increased cell proliferation, and new blood vessel formation; three of the classic hallmarks of cancer.
Our research focuses on three main areas:
- Understanding the molecular mechanisms regulating sphingolipid metabolism in cancer
- Developing agents that target sphingolipid metabolism as anti-cancer agents
- Defining the downstream pathways important for sphingolipid-mediated cancer cell signalling
Current research projects
- Defining the role of novel binding proteins in oncogenic signalling by sphingosine kinase: We have previously established that localisation of sphingosine kinase to the plasma membrane is critical for oncogenic signalling by this enzyme. Now we are seeking to understand how this localisation of sphingosine kinase is regulated via characterisation of the roles of a number of proteins that associate with this enzyme. This may identify new targets for anti-cancer therapy, particularly in ovarian cancer.
Characterising novel inhibitors of various enzymes involved in sphingolipid metabolism as potential therapies for acute myeloid leukaemia, multiple myeloma and glioblastoma: We recently developed novel chemical inhibitors of sphingolipid metabolic enzymes that show exciting anti-cancer activity in acute myeloid leukaemia, multiple myeloma and glioblastoma. Now we are further assessing and developing the existing, and second-generation inhibitors as anti-cancer and chemotherapy-sensitising agents.
- Characterising novel inhibitors of various enzymes involved in sphingolipid metabolism as potential therapies for acute myeloid leukaemia, multiple myeloma and glioblastoma: We recently developed novel chemical inhibitors of sphingolipid metabolic enzymes that show exciting anti-cancer activity in acute myeloid leukaemia, multiple myeloma and glioblastoma. Now we are further assessing and developing the existing, and second-generation inhibitors as anti-cancer and chemotherapy-sensitising agents.
Selected recent publications
Zhu W, Gliddon BL, Jarman KE, Moretti PAB, Tin T, Parise LV, Woodcock JM, Powell JA, Ruszkiewicz A, Pitman MR and Pitson SM (2017) CIB1 contributes to oncogenic signalling by Ras via modulation of sphingosine kinase 1. Oncogene 36, 2619–2627.
Powell JA, Lewis AC, Pitman MR, Wallington-Beddoe CT, Moretti PAB, Iarossi D, Samaraweera SE, Cummings N, Ramshaw H, Thomas D, Wei AH, Lopez AF, D'Andrea RJ, Lewis ID and Pitson SM (2017) Targeting sphingosine kinase 1 induces Mcl-1 dependent cell death in acute myeloid leukemia. Blood 129, 771–782.
Wallington-Beddoe CT, Bennett MK, Vandyke K, Davies L, Zebol JR, Moretti PAB, Pitman MR, Hewett DR, Zannettino ACW and Pitson SM (2017) Sphingosine kinase 2 inhibition synergises with bortezomib to target myeloma by enhancing endoplasmic reticulum stress. Oncotarget 8, 43602–43616.
Zhu W, Jarman K, Lokman NA, Neubauer HA, Davies LT, Gliddon BL, Taing H, Moretti PAB, Oehler M, Pitman MR and Pitson SM (2017) CIB2 negatively regulates oncogenic signaling in ovarian cancer via sphingosine kinase 1. Cancer Research 77, 4823-4834.
Lewis AC, Wallington-Beddoe CT, Powell JA and Pitson SM (2018) Targeting sphingolipid metabolism as an approach for combination therapies in haematological malignancies. Cell Death Discovery 5, 4.
Neubauer HA, Tea MN, Zebol JR, Gliddon BL, Stefanidis C, Moretti PAB, Pitman MR, Costabile M, Kular J, Stringer BW, Day BW, Samuel MS, Bonder CS, Powell JA and Pitson SM (2019) Cytoplasmic dynein regulates the subcellular localization of sphingosine kinase 2 to elicit tumor-suppressive functions in glioblastoma. Oncogene, in press (accepted 24 August 2018).