VAPB expression levels have been recently correlated with prognosis of breast cancer patients and induction of tumor cell proliferation in vitro and in vivo by VAPB has also been reported. VAPB is comprised by a MSP domain, which has the capacity to act as a signaling molecule: this domain is cleaved from the main protein and secreted, acting as a ligand of ephrin receptors (Eph). Eph (erythropoietin-producing hepatocellular carcinoma) are a large family of tyrosine kinase receptors with an important role in tissue organization during development, as well as in adult tissue homeostasis. Eph stimulation has been related with cancer and is closely involved in the development of the central nervous system. The EphA4 is a potential regulator of neurogenesis, and its expression is restricted to neural stem cells (NSC). It has also been shown that EphA4 expression keeps NSCs in an undifferentiated state. EphA4 is the receptor to which the MSP domain of VAPB binds. These ephrins and Eph receptors are expressed aberrantly in tumors and can dramatically affect tumor aggressiveness. Altogether, these findings support a possible mechanism by which the secreted MSP domain of VAPB can influence tumor development, particularly in the central nervous system, acting on the ephrin receptor EphA4. Medulloblastoma is the most common type of malignant embryonic brain tumor in children up to four years of age, accounting for about 18% of all pediatric brain tumors. It originates from undifferentiated primitive cells during neural development, involving signaling pathways relevant to the development of the nervous system. In addition, cancer cells with neural stem cell properties are present in medulloblastoma and are capable of generating new tumors. For these reasons, medulloblastoma is an interesting model to investigate this possible relationship between MSP-VAPB and EphA4. In this context, a possible new mechanism of cancer stem cell regulation by VAPB / Eph interaction, with impacts on medulloblastoma development, is hypothesized. Thus, the aim of this project is to evaluate whether the modulation of ephrin pathway by VAPB can regulate self-renewal of medulloblastoma stem cells and impact the tumor aggressiveness.
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