MRC National Institute for Medical Research, London
Science for Health
Cell survival depends on relative Wnt signalling
15 August 2011
Wnts are secreted glycolipoproteins that regulate many aspects of embryonic development, including tissue patterning, cell proliferation, differentiation and migration. Disturbances to Wnt activity lead to uncontrolled cell proliferation and are associated with many types of cancers. Wnt signalling has been extensively studied in the fruit fly, Drosophila melanogaster, particularly in wing primordia where Wingless, a Wnt homolog, regulates growth and cell fate decisions.
Jean-Paul Vincent (pictured) in NIMR’s Division of Developmental Neurobiology and Eugenia Piddini, now at the Gurdon Institute in Cambridge, have shown that Wingless is not intrinsically required for wing cell survival as previously thought. Wing cells that are genetically modified to prevent them from responding to Wingless do survive, as long as they are surrounded by other non-responsive or growth-compromised cells. Conversely, normal cells are eliminated if they are surrounded by cells that over-activate Wingless signal transduction. These results highlight the importance of relative, as opposed to absolute, levels of signalling.
Mutations in genes that lead to overactive Wnt signalling, such as APC or axin, are found in a variety of cancers. One striking finding reported in the paper is that, in Drosophila, APC or axin mutant cells trigger apoptosis in surrounding normal cells. An important mediator of this effect is the secreted phospholipase encoded by notum. By analogy, it is conceivable that APC mutant precancerous cells in humans could clear surrounding tissue thus making space for further growth. One must note however that although Notum is upregulated in many colon cancers, its functional significance in human cancer progression remains unknown.
Although our work is with Drosophila, it is likely to be relevant to human cancer. We have found that APC mutant cells kill normal cells and have identified a key secreted molecule required for this to occur. We have received MRCT funding to investigate the possibility that pharmacological inhibition of Notum could contribute to an anti-cancer therapy.
Jean-Paul Vincent
The role of Notum in Wnt-induced cell competition
Click image to view at full-size
Notum is predicted to act as secreted glypican-specific phospholipase, releasing glypicans from the cell surface, thus reducing the ability of Wingless to engage with the signalling receptors. As Notum’s expression is stimulated by Wingless signalling, it is a classical secreted feedback inhibitor of the pathway. Cells lacking APC or axin overactivate the Wingless pathway (dark green) irrespective of whether Wingless is present or not. As a result they secrete high levels of Notum, which reduces signalling in surrounding wild type cells (lighter green shading). The resulting steep difference in signalling triggers apoptosis (dark grey) in the weaker signalling cells.
Original article
Steep differences in Wingless signalling trigger Myc-independent competitive cell interactions (2011)
Jean-Paul Vincent, Golnar Kolahgar, Maria Gagliardi and Eugenia Piddini
Developmental Cell, 21(2):366-74. Publisher abstract
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