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

• 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
• 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

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.

项目概要/摘要 给定癌症类型内的单个细胞能够表达多种表型状态，从而导致 来自遗传、表观遗传、转录组和分子特征的潜在异质性。这怎么办 多样性的演变并影响治疗反应是癌症生物学中的一个基本问题。一个新兴的 形成这种异质性的机制是肿瘤内微环境生态位的进化， 支持癌症干细胞 (CSC) 状态。 CSC 由其功能能力定义，例如长期自我保护 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。 它们还被认为会导致对抗肿瘤疗法（例如放射疗法）的耐药性。胰管 腺癌 (PDAC) 的预后很差，5 年总生存率 <10%，迫切需要新的治疗方法 治疗策略。放射治疗是 PDAC 治疗不可或缺的一部分，但并非所有癌细胞都有反应。 确定放射抗性机制将改变 PDAC 的临床管理。使用胰脏 肿瘤模型中，我们的初步结果表明，一种癌细胞亚群产生的分泌性 Wnt 配体 在另一个癌细胞亚群中驱动 Lgr5+ 干细胞样状态，本质上形成一个支持性生态位，促进 胰腺肿瘤内的干细胞性。在这个提案中，我将测试 Wnt 驱动的细胞的中心假设 表型异质性和干性促进胰腺腺癌的放疗抵抗。我会 检查胰腺肿瘤细胞亚群在辐射抗性中的作用，包括 Lgr5+ 细胞（目的 1) 和 Wnt 生产利基（目标 2）。在目标 1 下，我将描述癌症干细胞的特性 胰腺癌中的 Lgr5+ 细胞、它们对放射治疗的相对抵抗力及其在肿瘤中的作用 人口重新增加。这些结果将确定 Lgr5+ 细胞是否是 CSC 以及放射抗性的驱动因素 确定的肿瘤并告知其分子特征，这可能提供针对这些肿瘤的额外手段 细胞。在目标 2 下，我将结合辐射研究 Wnt 产生生态位的靶向。 具体来说，我将结合辐射对 Wnt 通路进行遗传或药理学扰动 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的基本机制的了解。 异质性和辐射抗性，最终目标是转化这些发现并开发 改善 PDAC 患者的治疗策略。

项目成果

Systematic Comparison of Pancreatic Ductal Adenocarcinoma Models Identifies a Conserved Highly Plastic Basal Cell State.

胰腺导管腺癌模型的系统比较确定了保守的高可塑性基底细胞状态。

• 发表时间: 2022-10-04
• 影响因子: 11.2
• 作者: Pitter, Kenneth L;Grbovic;Joost, Simon;Singhal, Anupriya;Blum, Melissa;Wu, Katherine;Holm, Matilda;Ferrena, Alexander;Bhutkar, Arjun;Hudson, Anna;Lecomte, Nicolas;de Stanchina, Elisa;Chaligne, Ronan;Iacobuzio
• 通讯作者: Iacobuzio