RESUMO
How brain tumors progress from precancerous lesions to advanced cancers is not well understood. Using Ptch1(+/-) mice to study medulloblastoma progression, we found that Ptch1 loss of heterozygosity (LOH) is an early event that is associated with high levels of cell senescence in preneoplasia. In contrast, advanced tumors have evaded senescence. Remarkably, we discovered that the majority of advanced medulloblastomas display either spontaneous, somatic p53 mutations or Cdkn2a locus inactivation. Consistent with senescence evasion, these p53 mutations are always subsequent to Ptch1 LOH. Introduction of a p53 mutation prevents senescence, accelerates tumor formation, and increases medulloblastoma incidence. Altogether, our results show that evasion of senescence associated with Ptch1 LOH allows progression to advanced tumors.
Assuntos
Neoplasias Encefálicas/patologia , Senescência Celular , Meduloblastoma/patologia , Receptor Patched-1/metabolismo , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Cerebelo/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Metilação de DNA , Progressão da Doença , Proteínas Hedgehog/metabolismo , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Perda de Heterozigosidade , Meduloblastoma/metabolismo , Meduloblastoma/mortalidade , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Mutação de Sentido Incorreto , Receptor Patched-1/genética , Regiões Promotoras Genéticas , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Raios UltravioletaRESUMO
During cerebellar development, Sonic hedgehog (Shh) signaling drives the proliferation of granule cell precursors (GCPs). Aberrant activation of Shh signaling causes overproliferation of GCPs, leading to medulloblastoma. Although the Shh-binding protein Boc associates with the Shh receptor Ptch1 to mediate Shh signaling, whether Boc plays a role in medulloblastoma is unknown. Here, we show that BOC is upregulated in medulloblastomas and induces GCP proliferation. Conversely, Boc inactivation reduces proliferation and progression of early medulloblastomas to advanced tumors. Mechanistically, we find that Boc, through elevated Shh signaling, promotes high levels of DNA damage, an effect mediated by CyclinD1. High DNA damage in the presence of Boc increases the incidence of Ptch1 loss of heterozygosity, an important event in the progression from early to advanced medulloblastoma. Together, our results indicate that DNA damage promoted by Boc leads to the demise of its own coreceptor, Ptch1, and consequently medulloblastoma progression.