DEFINING THE MEDULLOBLASTOMA CANCER STEM CELL LINEAGE HIERARCHY BY NOTCH SIGNALING

项目摘要 髓母细胞瘤是儿童最常见的恶性脑肿瘤， 代表影响20%的髓母细胞瘤患者并赋予最差预后的分子亚型。 在诊断为第3组髓母细胞瘤的儿童中，10年生存率仅为20%， 传播总是致命的。髓母细胞瘤的幸存者经历了显著的神经和认知功能障碍， 由于其积极治疗的长期毒性而引起的并发症。 Notch信号传导高度参与干细胞稳态，并且越来越多地与癌症有关， 包括髓母细胞瘤。目前临床试验中的Notch途径抑制剂靶向γ-分泌酶， 在其受体活化的下游切割细胞内Notch蛋白。这些抑制剂不能 区分不同Notch家族成员的信号通路，并导致高水平的毒性。 因此，必须阐明不同Notch家族成员对肿瘤的功能贡献， 生长和繁殖，以开发特定的靶向治疗。 我们的数据表明，第3组髓母细胞瘤肿瘤细胞仅表达Notch 1或Notch 2， 以及表达两者的细胞。Notch 1信号的抑制导致转移性癌症的丧失， 剩余的原发性肿瘤具有较低的自我更新能力，而抑制Notch 2导致细胞增殖增加， 凋亡Notch 2在第3组髓母细胞瘤干细胞生长和转移中的作用仍然存在 未知 该项目将确定Notch 2与以下重要癌症干细胞特性的关系： 自我更新，2）癌症转移形成，和3）通过细胞凋亡调节的细胞存活。这些 这些区别对于理解第3组髓母细胞瘤的发育生物学很重要， 通过告知靶向Notch疗法如何影响癌症杀伤来改善髓母细胞瘤治疗。

PROJECT SUMMARY Medulloblastoma is the most common malignant brain tumor of childhood, and Group 3 medulloblastoma represents a molecular subtype which affects 20% of medulloblastoma patients and confers the worst prognosis. In children diagnosed with Group 3 medulloblastoma, ten-year survival is limited to 20% and metastatic dissemination is invariably fatal. Survivors of medulloblastoma experience significant neurological and cognitive complications due to the long-term toxicities of their aggressive treatment. Notch signaling is highly involved in stem cell homeostasis and has been increasingly implicated in cancer, including medulloblastoma. The current Notch pathway inhibitors in clinical trials target gamma-secretase, which cleaves the intracellular Notch protein downstream of its receptor activation. These inhibitors are unable to distinguish between the signaling pathways of different Notch family members, and result in high levels of toxicity. It is therefore imperative to delineate the functional contributions of different Notch family members to tumor growth and propagation in order to develop specific targeted therapies. Our data demonstrate that Group 3 medulloblastoma tumors possess cells that express only Notch1 or Notch2 and cells that express both. Inhibition of Notch1 signaling resulted in the loss of metastatic cancer, with the remaining primary tumor possessing less self-renewal ability, whereas inhibition of Notch2 led to increased cell apoptosis. The role of Notch2 in the growth and metastasis of Group 3 medulloblastoma stem cells remains unknown. The proposed project will determine the relationship of Notch2 to the important cancer stem cell properties of 1) self-renewal, 2) cancer metastasis formation, and 3) cell survival through the regulation of apoptosis. These distinctions are important in understanding the developmental biology of Group 3 medulloblastoma, and will improve medulloblastoma treatments by informing how targeted Notch therapies affect cancer killing.