Musashi-mediated control of pancreatic cancer growth and progression

描述（由申请人提供）：胰腺癌目前是美国第四大癌症死亡原因。尽管最近在全身治疗方面取得了一些进展，但生存率仍然很低，这在很大程度上是由于这种疾病的侵袭性和早期转移的倾向。因此，迫切需要确定新的治疗靶点，以更有效地阻止肿瘤的生长和扩散。为了确定癌症治疗的新方法，我们将重点放在被劫持的干细胞信号上，这些信号被劫持来驱动癌症的发生、繁殖和复发。使用这种方法，我们之前确定了干细胞命运决定因子Musashi （Msi）在血液恶性肿瘤的进展中至关重要。重要的是，我们最近发现Msi在胰腺癌小鼠模型和原发性患者样本中的胰腺癌细胞中高度表达。此外，我们的初步研究表明，Msi抑制在体外和异种移植中功能性地阻断胰腺癌细胞系以及患者样本的生长。这些数据使我们假设胰腺癌的生长和繁殖严重依赖于Msi。我们将通过确定1)Msi表达是否标志着“癌症干细胞”，即具有胰腺癌细胞增殖优先能力的细胞，2)Msi在基因工程小鼠模型中是否是胰腺癌增殖所必需的，以及3)Msi在原发性患者来源的异种移植物中是否是人类胰腺癌增殖所必需的。这些研究将有助于确定Msi是否是胰腺癌的关键调节因子，以及它是否可能是治疗的有效靶点。

DESCRIPTION (provided by applicant): Pancreatic cancer is now the 4th leading cause of cancer death in the United States. Despite some recent advances in systemic therapy, survival remains dismal in large part due to the aggressive nature of this disease and its propensity for early metastasis. Thus, there is a critical need to define new therapeutic targets that can more effectively block tumor growth and spread. To define new ways to approach cancer therapy we have focused on stem cell signals that are hijacked to drive cancer initiation, propagation, and recurrence. Using this approach we previously identified the stem cell fate determinant Musashi (Msi) as critically required for progression of hematologic malignancies. Importantly, we have recently found that Msi is highly expressed in pancreatic cancer cells in both mouse models of the disease and in primary patient samples. Further, our preliminary studies indicate that Msi inhibition functionally blocks the growth of pancreatic cancer cell lines as well as patient samples in vitro and in xenografts. These data have led us to hypothesize that pancreatic cancer growth and propagation is critically dependent on Msi. We will test this by determining 1) whether Msi expression marks "cancer stem cells", cells with preferential capacity for pancreatic cancer cell propagation, 2) whether Msi is necessary for propagation of pancreatic cancer in genetically engineered mouse models, and 3) whether Msi is necessary for human pancreatic cancer propagation in primary patient-derived xenografts. These studies will help define whether Msi is a key regulator of pancreatic cancer and if it may be an effective target for therapy.