CBIO-11. UPREGULATION OF THE TGF-β PATHWAY DRIVES TRANSFORMATION OF GLIOBLASTOMA INTO GLIOSARCOMA AND OSTEOSARCOMA

Abstract

INTRODUCTION

Gliosarcoma, a histopathological variant of glioblastoma, is defined by clonal biphasic differentiation into gliomatous and sarcomatous components. The underlying molecular mechanisms driving the transformation of glioblastoma to gliosarcoma are unclear. We observed a patient with glioblastoma that transformed to gliosarcoma at disease recurrence, and further evolved to an osteosarcoma at second disease relapse. Our objectives were to characterize the molecular mechanisms of tumor progression associated with phenotypic transformations.

METHODS

Tumor samples were collected at all three stages, and RNA sequencing was performed to capture the transcriptomic profiles. Sequential clonal evolution was confirmed by maintenance of identical PTEN mutation throughout the transformations. Applying EdgeR, DEseq2 and limma/voom to the data, we derived approximately 7,000 differentially-expressed genes by mutual comparisons between disease stages.

RESULTS

Functional analysis identified TGFB1 as a key regulator driving the tumor transformation -- a signature of 600 TGFB target genes and TGFB signaling pathways were upregulated. An active mesenchymal signature and significant increase in expression of mesenchymal transcriptional regulators (SNAI2, TWIST1) was observed at gliosarcoma stage. In addition, cellular migratory and angiogenic signatures were enhanced in the gliosarcoma stage. During transformation to gliosarcoma, neuronal developmental pathways, notch signaling, and PDGF signaling decreased. These results were validated via an independent external GBM and gliosarcoma dataset. The third stage of the tumor transformation was additionally characterized by upregulation of RUNX2 transcriptional regulator and an osteosarcoma network. These findings will be confirmed by examining additional primary and secondary gliosarcomas, and de novo osteosarcoma.

CONCLUSIONS

This unusual clinical case provides an opportunity to explore the modulators of sarcomatous transformation. Improved understanding of the underlying molecular mechanisms may contribute to identification of novel therapeutic targets in this disease.