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Cell Interactions and Cancer

Simona Parrinello

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Medical Research Council (MRC)
Our research focuses on understanding the cellular and molecular mechanisms underlying tissue regeneration and cancer in the nervous system. Although regeneration is limited in the central nervous system, the adult mammalian brain has retained two neurogenic niches containing neural stem cells that continuously produce new neurons and respond to injury or disease by further increasing neuronal production: the subventricular (SVZ) and subgranular zones (SGZ). In contrast, efficient regeneration occurs in the peripheral nervous system (PNS) in that after a cut, the nerve ends re-join and re-establish function. We have recently shown that Eph/ephrin-mediated cell-cell communication between Schwann cells and fibroblasts is critical for nerve repair as it induces the directional migration of Schwann cell groups into the injury site to guide axonal regrowth. Importantly, we found this process to be mediated by the transcription factor Sox2. Preliminary evidence suggests that a similar mechanism also regulates the SVZ niche. While it is well-established that ephrins control cell positioning by transiently modulating the cytoskeleton, our results indicate that ephrin signalling can also regulate cell behaviour more permanently by modifying gene expression. As most stem and progenitor cells express Ephs and Sox proteins, these findings have important implications for stem cell maintenance and differentiation, both of which require the coordination of positioning and cell identity. Moreover, given the similarities between nerve tumours and wounds and the identification of SVZ progenitors as cells of origin of many brain tumours, they suggest that Eph/ephrin signalling may mediate the interactions between cancer cells and their microenvironments to maintain the cancer stem cell properties of the tumour. Thus, gaining a greater understanding of these novel functions of Ephs should provide important insights into stem and tumour cells biology and suggest strategies for the treatment of nervous system pathology. Therefore, we are further exploring how cell-cell interactions modulate cell behaviour in regeneration and cancer with an emphasis on Eph/ephrin-dependent gene regulation. We use two parallel model systems of regenerative nervous tissue cell-cell interactions: 1) Schwann cells and fibroblasts in the injured peripheral nerve and neurofibromas; 2) neural progenitors and endothelial cells in the SVZ and gliomas. We have developed 2D and 3D co-culture systems that closely recapitulate the cell-cell interactions observed in the tissues and use these as primary tools to dissect the cellular and molecular mechanisms responsible. In parallel, we plan to use rodent animal models to validate the physiological relevance of our findings in vivo.

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