Stem cell signals in pancreatic adenocarcinoma metastasis and therapy resistance

胰腺癌转移和治疗耐药中的干细胞信号

基本信息

批准号：
9124131
负责人：
Nikki Katherine Lytle
金额：
$ 3.74万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9124131
关键词：
Biological Assay Blood Circulation Cancer Etiology Cancer Patient Cancer cell line Cells Cessation of life Chronic Myeloid Leukemia DNA Data Developed Countries Development Disease Disease Progression Distant Metastasis Dose Event Fluorouracil Frequencies Gene Expression Genetic Goals Hematologic Neoplasms Human Immunohistochemistry In Vitro Life Lung Malignant Neoplasms Malignant neoplasm of pancreas Medical Mouse Cell Line Mus Neoplasm Circulating Cells Neoplasm Metastasis Onset of illness Paclitaxel Pancreatic Adenocarcinoma Pancreatic Ductal Adenocarcinoma Pathogenesis Pathway interactions Patient-Focused Outcomes Patients Population Proteins RNA-Binding Proteins Refractory Regimen Reporter Residual Tumors Resistance Sampling Seeds Signal Transduction Site Solid Neoplasm Stage at Diagnosis Staining method Stains Stem cells Structure of thyroid parafollicular cell Survival Rate Tail Testing Time Veins Widespread Disease Work base cancer initiation chemotherapy fluorescence imaging gemcitabine improved in vivo leukemia liquid chromatography mass spectrometry mouse model nanoparticle neoplastic cell novel pancreatic cancer cells pancreatic neoplasm programs protein expression public health relevance response stem therapy resistant tripolyphosphate tumor tumor microenvironment tumor progression

项目摘要

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.

描述（由申请人提供）：胰腺腺癌 (PDAC) 是一种侵袭性恶性肿瘤，具有高转移率和较差的治疗反应，目前是发达国家癌症相关死亡的第四大原因，尽管人们努力改善治疗方案，但它仍然是癌症相关死亡的第四大原因。因此，确定促进疾病侵袭性和治疗耐药性的新靶点非常重要，我们的实验室和其他人之前已确定 RNA 结合蛋白 Musashi (Msi) 对于疾病的发展至关重要。我们已经证明，Msi2 在慢性粒细胞白血病的疾病进展过程中异常上调，并且抑制 Msi2 会导致白血病新生小鼠模型的总生存率显着增加。实体瘤的进展。测试了患者胰腺癌样本中的 Msi2 表达，并确定在 PDAC 的发病和发展过程中蛋白质表达确实增加。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 阻断显着减缓了肿瘤的发展。此外，我们确定 Msi2+ 胰腺癌细胞具有丰富的肿瘤增殖能力，这些数据表明 Msi2 在功能上有助于 PDAC 进展。 Msi2+ 细胞优先减少转移并在化疗中存活下来。为了测试这一点，我们的目标是 (1) 确定 Msi2+ 肿瘤细胞是否驱动转移的形成以及 Msi2 抑制转移负担，以及 (2) 确定 Msi2+ 细胞是否对化疗更具抵抗力并破译其机制。这些研究的结果有可能确定 PDAC 发病机制中的一个关键程序，并确定专门促进疾病侵袭性的细胞子集。