Title: Cell Growth Control and Regeneration: Roles in Cancer
Funder: Cancer Research UK

Abstract: We have developed powerful culture and in vivo model-systems to study two fundamental, but understudied, biological processes with important roles in cancer: cell growth and cell regeneration. By studying the molecular mechanisms controlling these processes and how they are deregulated in cancer, we aim to identify new targets for therapeutics. Schwann cells are the main glial cells of the peripheral nervous system. Properties of these cells make them a powerful model system for studying two fundamental biological processes: (1) Cell growth (2) Cell regeneration. (1) The formation of a tumour mass requires deregulated growth controls since mammalian cells require instructive signals to add volume/mass. How extracellular signals regulate cell size/mass and how these are deregulated in cancer remain poorly understood despite their importance for tumour development and maintenance. We have identified extracellular factors that cooperate to strongly drive cell growth. Moreover, unexpectedly, we have found that the addition of cell mass is regulated separately from cell volume. These findings raise fundamental questions about how cell growth and cell size are regulated and coordinated. We have also found that oncogenes cooperate to drive growth and identified a novel role for the RB-family in this process. The mechanisms involved, however, remain unclear. Key aims of my proposed programme of research are to identify the signalling pathways involved in normal and oncogenic growth and determine how these processes are regulated and coordinated. Using a combination of cell-based screens, expression and biochemical analysis and imaging techniques we will identify key regulatory molecules and determine their roles in cancer. (2) Schwann cells are regenerative in that to produce new cells, they dedifferentiate from a quiescent, highly specialised cell-state to a progenitor-like cell. Axonal signals regulate this switch in cell-state and so understanding the mechanisms underlying Schwann cell/axonal interactions is key to understanding Schwann cell tumourigenesis. Neurofibromatosis Type-1 (NF1) is a common familial disorder characterised by multiple Schwann cell-derived tumours. The NF1 gene encodes a Ras-GAP and elevated Ras-signalling is important for tumour development. We have found that activated Ras/Raf/ERK signalling drives the dedifferentiation of Schwann cells and disrupts Schwann cell/axonal interactions. We found that loss of axonal interactions results from the downregulation of semaphorin4F, identifying a novel role for this family of molecules in mediating axonal/glial interactions and in cancer. Major aims of this programme are to determine the role of semaphorins in regulating Schwann cell/axonal interactions and how these controls are lost in cancer. Moreover, we will continue to explore, particularly in vivo, the mechanisms whereby NF1 loss and Ras/Raf/ERK signalling can drive tumour formation. These studies will exploit mouse models that we have developed, together with our in vitro co-culture systems, to explore the development of and potential treatments for these tumours. Last updated 21/07/2010


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS