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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结