Stem cell signals in pancreatic adenocarcinoma metastasis and therapy resistance

 描述(申请人提供)：胰腺癌(PDAC)是一种侵袭性极强的恶性肿瘤，转移率高，治疗反应差。它目前是发达国家癌症相关死亡的第四大原因，尽管努力改进治疗方案，但总体存活率的中位数仍为一年。因此，重要的是确定促进疾病侵袭性和治疗抵抗力的新靶点。我们的实验室和其他人之前已经确定RNA结合蛋白Musashi(MSI)对多种恶性肿瘤的发展至关重要。我们已经证明，在慢性髓细胞白血病的疾病进展过程中，MSI2异常上调，抑制MSI2导致新生白血病小鼠模型的总存活率显着增加。然而，目前尚不清楚MSI2是否在实体肿瘤的进展中起重要作用。在这方面，我们 检测胰腺癌患者样本中MSI2的表达，并确定确实在PDAC的发生和发展过程中蛋白质表达增加。通过利用与MSI2-/-小鼠杂交的胰腺癌遗传小鼠模型，我们发现MSI2阻断显著减缓了肿瘤的发展，并导致了总存活率的提高。此外，我们还确定MSI2+胰腺癌细胞具有丰富的肿瘤增殖能力。这些数据表明，MSI2在功能上促进了PDAC的进展。因此，我们假设MSI2+细胞优先转移并在化疗中存活。为了测试这一点，我们的目标是(1)确定MSI2+肿瘤细胞是否推动转移的形成，以及MSI2抑制是否减少转移负担，以及(2)确定MSI2+细胞是否对化疗更具抵抗力，并破译它们优先存活的机制。这些研究的结果有可能确定PDAC发病机制中的关键程序，并确定特定促进疾病侵袭性的细胞子集。

 DESCRIPTION (provided by applicant): Pancreatic adenocarcinoma (PDAC) is a remarkably aggressive malignancy associated with high rates of metastasis and poor therapy response. It is currently the 4th leading cause of cancer related deaths in developed countries and despite efforts to improve treatment options, the median overall survival remains <1 year. Therefore it is important to identify new targets that promote disease aggressiveness and therapy resistance. Our lab and others have previously identified the RNA-binding protein Musashi (Msi) as critical for the development of multiple malignancies. We have demonstrated that Msi2 is aberrantly upregulated during disease progression in chronic myeloid leukemia and inhibition of Msi2 results in a significant increase in overall survival in de novo mouse models of leukemia. However, it was unclear if Msi2 is important in the progression of solid tumors. In this regard, we tested for Msi2 expression in patient pancreatic cancer samples and determined that indeed protein expression increases during the onset and development of PDAC. By utilizing a genetic mouse model of pancreatic cancer crossed to Msi2-/- mice, we found that Msi2 blockade significantly slows tumor development and results in increased overall survival. Moreover, we determined that Msi2+ pancreatic cancer cells are enriched for tumor-propagating ability. These data suggest that Msi2 functionally contributes to PDAC progression. Therefore, we hypothesize that Msi2+ cells preferentially metastasize and survive chemotherapy. To test this we aim to (1) determine if Msi2+ tumor cells drive formation of metastasis and if Msi2 inhibition reduces metastatic burden, and (2) determine if Msi2+ cells are more resistant to chemotherapies and decipher the mechanisms by which they preferentially survive. The results of these studies have the potential to identify a key program in PDAC pathogenesis and define a subset of cells that specifically promote disease aggressiveness.