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Cellular phenotypic heterogeneity and resistance to radiotherapy in pancreatic adenocarcinoma

胰腺腺癌的细胞表型异质性和放疗耐药性

基本信息

批准号：
10693293
负责人：
Kenneth L Pitter
金额：
$ 39.38万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-22 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10693293
关键词：
Ablation Acyltransferase Address Adult Animal Experimentation Animals Award Biochemical Biological Biological Assay Cancer Biology Career Mobility Cell Differentiation process Cells Characteristics Chemotherapy and/or radiation Clinic Clinical Clinical Management Colorectal Adenocarcinoma Core Facility Data Eligibility Determination Enzymes Epigenetic Process Evolution Faculty Gene Expression Profiling Genetic Genetic Heterogeneity Genetically Engineered Mouse Goals Heterogeneity Human Immunocompetent Immunotherapy Individual Institution LGR5 gene Laboratories Laboratory Research Letters Ligands Localized Disease Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of pancreas Memorial Sloan-Kettering Cancer Center Mentors Methods Minority Molecular Mus Operative Surgical Procedures Pancreas Pancreatic Adenocarcinoma Pancreatic Ductal Adenocarcinoma Pancreatic Injury Pathway interactions Patients Phenotype Population Porcupines Positioning Attribute Postdoctoral Fellow Productivity Prognosis Property Radiation Radiation therapy Radiation-Sensitizing Agents Radiosensitization Research Resistance Resources Role Secure Shapes Stimulation of Cell Proliferation Testing Therapeutic Training Translating Translations WNT Signaling Pathway Work cancer cell cancer heterogeneity cancer stem cell cancer type cell type chemotherapy conventional therapy disorder control experience graduate student immune activation improved inhibitor insight interest member novel therapeutic intervention palmitoylation pancreatic cancer cells pancreatic cancer model pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model pancreatic neoplasm pharmacologic professor programs radiation resistance response self-renewal small molecule stem stem-like cell stemness targeted treatment tenure track therapeutic evaluation therapeutic target therapy resistant transcriptomics treatment response treatment strategy tumor tumor growth tumor heterogeneity tumor microenvironment

项目摘要

PROJECT SUMMARY/ABSTRACT Individual cells within a given cancer type are capable of expressing a diversity of phenotypic states resulting from an underlying heterogeneity of genetic, epigenetic, transcriptomic, and molecular features. How this diversity evolves and influences therapeutic response is an essential question in cancer biology. One emerging mechanism of developing such heterogeneity is the evolution of microenvironmental niches within tumors that support a cancer stem cell (CSC) state. CSCs are defined by their functional capabilities such as long-term self- renewal, the capacity to give rise to a range of differentiated cell types, and enhanced tumor-forming ability. They are also believed to drive resistance to anti-tumor therapies, such as radiation therapy. Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, with a 5-year overall survival of <10% and a dire need for novel therapeutic strategies. Radiation is an integral part of PDAC therapy, however not all cancer cells respond. Identifying mechanisms of radioresistance would transform the clinical management of PDAC. Using pancreatic tumor models, our preliminary results suggest that secreted Wnt ligands produced by one cancer cell subset drive a Lgr5+ stem-like state in another cancer cell subset, in essence forming a supportive niche that promotes stemness within pancreatic tumors. In this proposal, I will test the central hypothesis that Wnt-driven cellular phenotypic heterogeneity and stemness promote radiotherapy resistance in pancreatic adenocarcinoma. I will examine the role of pancreatic tumor cell subpopulations in radiation resistance, including the Lgr5+ cells (Aim 1) and the Wnt producing niche (Aim 2). Under Aim 1, I will characterize the cancer stem cell properties of Lgr5+ cells in pancreatic cancer, their relative resistance to radiation therapy, and their role in tumor repopulation. These results will determine whether Lgr5+ cells are CSCs and drivers of radioresistance in established tumors and inform their molecular characteristics, which may provide added means to target these cells. Under Aim 2, I will investigate the targeting of the Wnt-producing niche in combination with radiation. Specifically, I will use genetic or pharmacologic perturbation of the Wnt pathway in combination with radiation and assay tumor response and animal survival. These efforts will test the therapeutic potential of Wnt inhibitors as radiosensitizers in PDAC. Collectively, this work will facilitate basic mechanistic insights into both cellular heterogeneity and radioresistance, with the ultimate goal of translating these discoveries and developing improved treatment strategies for PDAC patients.

项目总结/摘要给定癌症类型中的单个细胞能够表达多种表型状态，从而遗传、表观遗传、转录组和分子特征的潜在异质性。这如何多样性演变和影响治疗反应是癌症生物学中的基本问题。一种新兴发展这种异质性的机制是肿瘤内微环境生态位的演变，支持癌症干细胞（CSC）状态。CSC由其功能性能力定义，例如长期自我管理能力。更新，产生一系列分化细胞类型的能力，以及增强的肿瘤形成能力。它们也被认为会导致抗肿瘤治疗的耐药性，如放射治疗。胰腺导管腺癌（PDAC）预后不佳，5年总生存率<10%，迫切需要新的治疗方法。治疗策略放射是PDAC治疗的一个组成部分，但并非所有癌细胞都有反应。确定放射抗性的机制将改变PDAC的临床管理。使用胰腺在肿瘤模型中，我们的初步结果表明，一种癌细胞亚群分泌的Wnt配体在另一个癌细胞亚群中驱动Lgr 5+干细胞样状态，本质上形成一个支持性的小生境，胰腺肿瘤内的干性。在这个建议中，我将测试中心假设，即Wnt驱动的细胞表型异质性和干性促进胰腺癌的放射治疗抵抗。我会检查胰腺肿瘤细胞亚群在放射抗性中的作用，包括Lgr 5+细胞（Aim 1)和Wnt生产生态位（Aim 2）。在目标1下，我将描述以下癌症干细胞的特性：胰腺癌中的LGR 5+细胞、它们对放射治疗的相对抵抗性及其在肿瘤中的作用再繁殖这些结果将确定Lgr 5+细胞是否是CSC和辐射抗性的驱动因素。建立的肿瘤，并告知他们的分子特征，这可能提供额外的手段，以针对这些细胞在目标2下，我将研究结合辐射的Wnt产生生态位的靶向。具体来说，我将使用Wnt途径的遗传或药理学干扰与辐射相结合并测定肿瘤反应和动物存活率。这些努力将测试Wnt抑制剂的治疗潜力作为PDAC中的放射增敏剂。总的来说，这项工作将促进对细胞和细胞生物学的基本机械见解。异质性和辐射抗性，最终目标是转化这些发现，改善PDAC患者的治疗策略。