STMC-02. TUMOR RECURRENCE FROM CANCER STEM-LIKE CELLS POST-RADIATION IS REGULATED BY THE Shh-YAP-YB1-IGF2 AXIS IN MEDULLOBLASTOMA

Sonic hedgehog (Shh)-mediated medulloblastoma growth requires IGF2 (Insulin-like Growth Factor 2) and we have shown that over-expression of Yes Associated Protein (YAP1) induces IGF2 expression as a part of YAP’s radiation resistance mechanism in mouse Shh-medulloblastoma cells and Shh-induced cerebellar granule neural precursors (CGNPs), proposed cells-of-origin for the SHH molecular subclass of medulloblastoma (1). The peri-vascular niche, a microenvironmental niche proposed to house so-called tumor re-populating cells that survive radiation and contribute to medulloblastoma recurrence, showed high levels of YAP and IGF2. The mechanism of IGF2 induction downstream of YAP is not understood. Using chromatin-IP and promoter binding-protein analyses, we have found that Y-box protein-1 (YB1) is a major regulator IGF2 expression downstream of YAP and Sonic Hedgehog signaling (2), and YB1 also localizes to the peri-vascular niche. To better comprehend how YAP, YB1, and IGF2 regulate peri-vascular niche cell survival, we have developed an ex vivo approach using organotypic brain tumor slice cultures. We observed that the stem-like population of perivascular niche increases markedly following exposure to radiation, and that targeting any component of the YAP1-YB1-IGF2 axis increases the level of cell death within the tumor microenvironment and reduces expansion of stem-like cell population. Our findings strongly suggest that therapeutic targeting of this pathway could be ...
Source: Neuro-Oncology - Category: Cancer & Oncology Authors: Tags: STEM CELLS Source Type: research