Abstract
Sonic hedgehog (SHH) medulloblastoma (MB) subtype is driven by a proliferative CD15+ tumor propagating cell (TPC), also considered in the literature as a putative cancer stem cell (CSC). Despite considerable research, much of the biology of this TPC remains unknown. We report evidence that phosphatase and tensin homolog (PTEN) and phosphoinositide 3-kinase (PI-3K) play a crucial role in the propagation, survival and potential response to therapy in this CD15+ CSC/TPC-driven malignant disease. Using the ND2-SmoA1 transgenic mouse model for MB, mouse genetics and patient-derived xenografts (PDXs), we demonstrate that the CD15+TPCs are 1) obligately required for SmoA1Tg-driven tumorigenicity 2) regulated by PTEN and PI-3K signaling 3) selectively sensitive to the cytotoxic effects of pan PI-3K inhibitors in vitro and in vivo but resistant to chemotherapy 4) in the SmoA1Tg mouse model are genomically similar to the SHH human MB subgroup. The results provide the first evidence that PTEN plays a role in MB TPC signaling and biology and that PI-3K inhibitors target and suppress the survival and proliferation of cells within the mouse and human CD15+ cancer stem cell compartment. In contrast, CD15+ TPCs are resistant to cisplatinum, temozolomide and the SHH inhibitor, NVP-LDE-225, agents currently used in treatment of medulloblastoma. These studies validate the therapeutic efficacy of pan PI-3K inhibitors in the treatment of CD15+ TPC dependent medulloblastoma and suggest a sequential combination of PI-3K inhibitors and chemotherapy will have augmented efficacy in the treatment of this disease.
Highlights
Medulloblastoma (MB) is an aggressive cerebellar tumor and the most common pediatric brain malignancy [1, 2]
phosphoinositide 3-kinase (PI-3K) signaling is highly elevated in CD15+ tumor propagating cell (TPC) isolated from SmoA1 Tg medulloblastoma mouse model
An orthotopic transplantation assay was established in which SmoA1 phosphatase and tensin homolog (PTEN) +/+ tumor cells were sorted into CD15+ and CD15− fractions, and 2 x 106 cells from each fraction were stereotaxically implanted into the cerebellum of nude/nu-nu mice
Summary
Medulloblastoma (MB) is an aggressive cerebellar tumor and the most common pediatric brain malignancy [1, 2]. Several groups [4,5,6,7,8] have performed gene expression profiling and DNA-copy-number analysis of MB, and have identified at least four major subtypes of the disease: WNT, Sonic hedgehog (SHH), Group C, and Group D. These molecular subtypes have distinct characteristics in terms of gene expression, mutational profiles, epidemiology, and prognosis. Recent genomic analysis of medulloblastoma tumors revealed that PI-3K mutation (PIK3CA, PTEN, PIK3C2G) is frequent in SHH subgroup tumors [21, 22]. Out of 133 SHH MB tumors profiled, PI-3K pathway is mutated in >5% of SHH MBs [21, 22]
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