Linking mitogenic sonic hedgehog signaling to the oncogene Yap 1 in neural stem/progenitor cells and medulloblastoma.

Medulloblastoma, the most common solid pediatric tumor, arises in the cerebellum.  This brain region controls posture and coordination.  The development of the cerebellum is marked by rapid division of immature neurons, medulloblastoma "cells of origin".  We want to understand how their fast division promotes their conversion from normal young neurons into tumor cells.  We treated immature mouse cerebellum cells with a protein called Sonic Hedgehog (Shh), which causes medulloblastomas.   The Shh caused these cells to make another protein, Yap1.  In many cancers, Yap1 is found at very high levels.  Causing Yap1 to be elevated in non-cancer cells makes them take on tumor cell properties.  We found reports that Yap1 is present at high levels in medulloblastomas caused by over-active Shh.  When we studied medulloblastomas that occurred in mice with over-active Shh, we saw Yap1 in tumor cells located near blood vessels.  Others have shown that such vessel-associated tumor cells are medulloblastoma "cancer stem cells"-- cells that can re-grow the tumor even if it is treated with radiation or chemotherapy.  Yap1 activity could be part of the program these cells use to resist therapy and proliferate.  How Sonic hedgehog causes Yap1 to increase in cells, how Yap1 is involved in the rapid division of young neurons, and how Yap1 is involved in medulloblastoma are the unanswered questions that we hope to resolve.  This work may help us identify whether Yap1 is a molecule whose activity we could block to stop the tumor from growing or recurring.