Abstract 996: Metastasis and tumor recurrence from rare SOX9-positive cells in Group 4 medulloblastoma
Authors: Savov Vasil , Fotaki Grammatiki , Remke Marc , Dubuc Adrian M. , Ramaswamy Vijay , Cancer Matko , Weishaupt Holger , Taylor Michael D. , Swartling Fredrik J. 
Published: May 2015

Tumor recurrence is the main cause of death in children with medulloblastoma (MB). MYCN is a marker for poor prognosis which is amplified in SHH and Group 4 but rarely in WNT and Group 3 subgroups of MB. The exact mechanisms for MB relapse are not known but recent findings (Ramaswamy et al. Lancet Oncol., 2013) suggest temporal differences within the four MB subgroups. For instance, SHH tumors recur locally while SHH-independent Group 4 tumors develop distant metastases. In order to study these processes further, we used a previously described transgenic mouse model of MYCN-driven SHH-independent MB (GTML mouse) to recreate the metastatic recurrence of such brain tumors in vivo.

We previously showed that the expression of SOX9 transcription factor correlates well with SHH tumors and that only a few scattered SOX9-positive cells are found in SHH-independent GTML tumors similarly to Group 4 human MB. By using a combination of Tet-ON and Tet-OFF inducible systems we managed to target this rare population of SOX9-positive GTML tumor cells in vivo. These cells were able to form a distant recurrence after the tumor bulk in the mice was removed by using dox-inducible oncogene depletion. These relapses showed similar morphology and immunoreactivity of defined MB markers but presented generally higher levels of SOX9 compared to the primary GTML tumors.

Additionally, we overexpressed SOX9 in cerebellar stem cells transfected with a mutationally stabilized MYCNT58A and injected them back into the cerebellum of adult mice. Surprisingly, the MB-like tumors that formed migrated and developed in the forebrain in contrast to the cerebellar tumors induced by the same cells transfected with MYCNT58A only. These findings suggest that increased levels of SOX9 drives migration of MYCN-driven MB cells. A similar correlation was found in Group 4 MB patients where isolated metastases had consistently higher SOX9 levels as compared to the corresponding primary tumor.

Significance: We have developed a new mouse model for MB recurrence. We show how a rare population of SOX9-positive cells in SHH-independent MB is capable of initiating recurrence after primary tumor removal. The relapsed MB has similar characteristics to the initial tumor but develops at a distant site in the brain, in line with recent data from human tumors. Further characterization of cells with such properties will help to improve our understanding of the mechanisms behind metastatic MB recurrence and to develop treatments against those migrating cell populations.

Citation Format: Vasil Savov, Grammatiki Fotaki, Marc Remke, Adrian M. Dubuc, Vijay Ramaswamy, Matko Cancer, Holger Weishaupt, Michael D. Taylor, Fredrik J. Swartling. Metastasis and tumor recurrence from rare SOX9-positive cells in Group 4 medulloblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 996. doi:10.1158/1538-7445.AM2014-996