Targeting stem-like cells and their niche in pancreatic cancer

靶向干细胞样细胞及其在胰腺癌中的定位

• 批准号: 10083206
• 负责人: Tuomas Tammela
• 金额: $ 50.42万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-08 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10083206
• 关键词: Ablation; Acyltransferase; Adult; Alleles; Antineoplastic Agents; Biology; Cell Compartmentation; Cells; Characteristics; Colorectal Adenocarcinoma; Complex; Cyclodextrins; Data; Desmoplastic; Development; Diagnosis; Drug Delivery Systems; Enzymes; Failure; Gene Expression; Gene Expression Profiling; Genetic; Genetically Engineered Mouse; Growth Factor; Heterogeneity; Human; Immune; In Vitro; LGR5 gene; Lead; Ligands; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of pancreas; Methods; Modeling; Molecular; Mus; Mutation; Neoplasm Metastasis; Normal tissue morphology; Pancreas; Pancreatic Ductal Adenocarcinoma; Patients; Phenotype; Porcupines; Post-Translational Protein Processing; Primary Neoplasm; Property; Proteomics; Reporter; Reporting; Resistance; Role; Signal Pathway; Signal Transduction; Solid Neoplasm; Testing; Therapeutic; Toxic effect; Translating; WNT Signaling Pathway; Xenograft Model; addiction; cancer cell; cancer therapy; cell stroma; chemotherapy; conventional therapy; improved; in vivo; inhibitor/antagonist; insight; mutant; novel therapeutic intervention; novel therapeutics; pancreatic cancer cells; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; pancreatic neoplasm; response; small molecule; small molecule inhibitor; stem; stem cells; stem-like cell; subcutaneous; therapeutic evaluation; therapeutic target; therapy resistant; tumor; tumor progression; ubiquitin ligase

PROJECT SUMMARY Less than 8% of pancreatic ductal adenocarcinoma (PDAC) patients are alive 5 years after diagnosis. PDAC is typically diagnosed at an advanced stage, limiting treatment options. Chemotherapies are the mainstay for ad- vanced PDAC, though they produce incomplete responses. Thus, development of novel therapies for PDAC patients is urgently needed. A possible explanation for failure of standard chemotherapies in PDAC is cellular phenotypic heterogeneity within tumors. Heterogeneity may enable subpopulations of cells to survive therapy and repopulate the tumor. Cancer stem-like cells (CSCs) have been described in multiple solid tumor types. CSCs have robust proliferative potential and are typically resistant to cancer therapies. Elimination or re-differ- entiation of cancer stem-like cells is an attractive strategy: By homogenizing cancer cell phenotypes within tu- mors, such therapies may suppress tumor progression and lead to improved responses to conventional thera- pies. Our pilot data suggest that secreted Wnt ligands produced by one cancer cell subpopulation drive a stem- like state in another cancer cell subpopulation, in essence forming a specialized microenvironment, or niche, within pancreatic tumors that maintains CSCs. We found that CSCs express Wnt target gene Lgr5, whereas niche cells are marked by Porcupine, an enzyme that post-translationally modifies Wnt. Hypothesis: Disrupting CSC and niche cells can translate into novel therapeutic strategies for PDAC patients. We propose to identify mechanisms that drive Lgr5+ CSC and Porcupine+ niche cell states and to explore the potential of Wnt inhibi- tors in PDAC therapy. These studies have the potential to translate into new PDAC therapies. Aim 1. Interro- gate function of Lgr5+ stem-like PDAC cells. We will profile Lgr5+ pancreatic cancer cells and evaluate ability to functionally contribute to PDAC progression, metastasis, and resistance to chemotherapy. We will perform lineage-tracing and -ablation, and gene expression and proteomic profiling of Lgr5+ cells in genetically engi- neered mouse PDAC tumors. Results will determine whether Lgr5+ cells are CSCs in established tumors and inform their molecular characteristics, which may provide added means to target these cells. Aim 2. Elucidate biology of Porcupine+ PDAC niche cells. We will identify molecular mechanisms that drive Porcupine+ niche cell state. We will use Porcupine reporter allele to ablate these cells in PDAC to evaluate role in tumor progres- sion, and isolate niche cells for proteomic and gene expression profiling. Results will provide insights into role of Porcupine+ cells in PDAC progression and how to target them. Aim 3. Therapeutically target Wnt signaling in PDAC. We will target Wnt signaling by using small molecule inhibitors of Porcupine as single agents and in combination with chemotherapy. To improve delivery of these drugs into desmoplastic PDAC tumors, we will complex them with cyclodextrin carrier molecules. These therapies will be tested in orthotopic mouse and pa- tient-derived xenograft models of PDAC in RNF43 wild-type and mutant PDAC. These efforts will test thera- peutic potential of Wnt inhibitors in PDAC, which may sensitize pancreatic tumors to chemotherapy.

项目摘要 诊断后5年，不到8％的胰腺导管腺癌（PDAC）患者还活着。 PDAC是 通常在高级阶段诊断，限制治疗方案。化学疗法是AD- Vanced PDAC，尽管它们产生不完全的响应。因此，开发PDAC的新型疗法 迫切需要患者。 PDAC中标准化疗失败的可能解释是细胞 肿瘤内表型异质性。异质性可能使细胞的亚群生存于治疗 并重新填充肿瘤。已经描述了多种实体瘤类型中的癌症干细胞（CSC）。 CSC具有强大的增殖潜力，通常对癌症疗法具有抵抗力。消除或重新分辨 - 癌症样细胞的诱导是一个有吸引力的策略：通过使癌细胞表型在Tu-中匀浆 MORS，这种疗法可能抑制肿瘤的进展，并改善对常规疗法的反应 派。我们的试点数据表明，一个癌细胞亚群生成的分泌的Wnt配体驱动了茎 就像在另一个癌细胞亚群中的状态一样，本质上形成了专门的微环境或利基市场 在维持CSC的胰腺肿瘤内。我们发现CSC表达Wnt靶基因LGR5，而 利基细胞由豪猪（Potcupine）标记，豪猪是一种在翻译后修饰Wnt的酶。假设：破坏 CSC和利基细胞可以转化为PDAC患者的新型治疗策略。我们建议确定 驱动LGR5+ CSC和豪猪+细胞态的机制，并探索Wnt抑制的潜力 PDAC治疗中的TOR。这些研究有可能转化为新的PDAC疗法。目标1。 LGR5+ Stem样PDAC细胞的栅极功能。我们将介绍LGR5+胰腺癌细胞并评估能力 在功能上有助于PDAC的进展，转移和对化学疗法的抗性。我们将表演 遗传性工程中LGR5+细胞的谱系追踪和启动，基因表达和蛋白质组学分析 Neered小鼠PDAC肿瘤。结果将确定LGR5+细胞在已建立的肿瘤中是否是CSC和 告知其分子特征，这可能会提供靶向这些细胞的添加手段。目标2。阐明 豪猪+ PDAC细胞的生物学。我们将确定驱动豪猪+利基市场的分子机制 细胞状态。我们将使用豪猪记者等位基因在PDAC中消除这些细胞，以评估在肿瘤progres- 用于蛋白质组学和基因表达分析的sion和分离菌细胞。结果将提供有关角色的见解 PDAC进展中的豪猪+细胞以及如何靶向它们。目标3。治疗靶向Wnt信号 在PDAC。我们将通过使用豪猪的小分子抑制剂作为单个药物和在 结合化学疗法。为了改善这些药物的递送到脱肿瘤的PDAC肿瘤中，我们将 将它们与环糊精载体分子相结合。这些疗法将在原位小鼠和PA-中进行测试 RNF43野生型和突变体PDAC中PDAC的Tient衍生的异种移植模型。这些努力将测试 Wnt抑制剂在PDAC中的质量潜力，这可能使胰腺肿瘤对化学疗法敏感。