Elucidation and targeting of paracrine cascades in PDAC

PDAC 中旁分泌级联的阐明和靶向

基本信息

批准号：
10518098
负责人：
Gulam Abbas Manji
金额：
$ 98.55万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10518098
关键词：
Algorithms Allografting Behavior Biological Models Blocking Antibodies Blood Blood specimen CCR1 gene CD8-Positive T-Lymphocytes Cells Clinical Clinical Services Clinical Trials Coculture Techniques Communication Complex Computational algorithm Cytotoxic Chemotherapy Data Data Set Desmoplastic Diffusion Dissection Drug Combinations Drug Delivery Systems Effector Cell Electronic Medical Records and Genomics Network Elements Endothelium Erinaceidae Fibroblasts Genetic Transcription Genetically Engineered Mouse Growth Heterogeneity Hospitals Human Immunosuppression Immunotherapy Individual Intercellular Fluid Intercept Investigation KPC model Lead Ligands Link Logic Lymphocyte Lymphoid Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of pancreas Mediating Metabolic Methods Modeling Myelogenous Myeloid Cells Myeloid-derived suppressor cells Myofibroblast New York Olives - dietary Outcome Study Paint Pancreas Pancreatic Ductal Adenocarcinoma Paracrine Communication Pathway Analysis Pathway interactions Patients Perfusion Phenotype Population Presbyterian Church Primary Cell Cultures Recombinant Proteins Regimen Regulation Reporting Resources Role SHH gene Sampling Series Signal Transduction Slice Spleen Stromal Cells Stromal Neoplasm System Systems Biology Techniques Testing Therapeutic Therapeutic Agents Therapeutic Intervention Tissue Sample Tissues Toxic effect Tumor Tissue Validation Work analytical tool angiogenesis base cancer cell cell type chemokine clinical translation computational suite computerized tools conditioning cytotoxic drug efficacy functional outcomes immunosuppressed improved in vivo inhibitor innovation member mouse model multidisciplinary mutant novel overexpression pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model pancreatic neoplasm paracrine pre-clinical receptor response single cell technology single-cell RNA sequencing targeted agent targeted treatment tool treatment response tumor tumor microenvironment

项目摘要

Abstract Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies due largely to their lack of response to current cytotoxic, targeted, and immune therapies. PDAC tumor tissues harbor an expansive, desmoplastic stroma that both suppresses angiogenesis and limits perfusion and diffusion. Consequently, delivery of therapeutic agents through systemic administration is impeded, lowering drug efficacy and increasing general toxicity. Indeed, multiple components of the PDAC stroma support its survival and growth, for example by conditioning a locally immunosuppressed microenvironment that facilitates tumor survival. Conversely, we previously showed that at least some elements of the tumor stromal restrain PDAC growth and progression, for example Hedgehog pathway-responsive myofibroblasts. Early attempts to modulate the PDAC stroma in order to facilitate drug delivery failed upon clinical translation. Post-clinical trials ultimately demonstrated that stromal remodulation upon inhibition of individual pathways can lead to unpredictable consequences in multiple additional cell types. Based on these data, we hypothesize that individual paracrine pathways typically link together to form “paracrine cascades” that propagate through multiple pathways and cell types. We advance that reconstructing these paracrine cascades offers both the opportunity to better understand the consequences of therapeutic intervention and also to infer candidate targets that act on a broad range of cell types within the PDAC TME to enact stromal remodulation. In order to test this, we will make use of a series of innovative systems biology tools built by members of our transdisciplinary team. These include a suite of algorithms leveraging the computational field of regulatory network analysis, as well as technically innovative techniques for studying outcomes in single cell datasets. Moreover, we will acquire unique dataset from samples collected by members of our multidisciplinary clinical service at the Pancreas Center of New York Presbyterian Hospital. These include acquiring human PDAC tumor interstitial fluid and generating matched sets of tumor, normal pancreas, spleen, and blood samples from PDAC patients. We will also routinely utilize fresh PDAC tissue samples to make tumor “explants” a novel ex vivo model system for the short-term, medium throughput study of PDAC. This new model system enables the dissection of complex multi-cellular phenotypes in ways that are not possible through study of intact tumors or co-cultures of purified cell types Using these approaches, we will reconstruct the network of paracrine cascades in PDAC and validate selected candidates experimentally. We will also test a specific candidate pathway uncovered through study of the Hh pathway that connects myofibroblasts to myeloid derived suppressor cells and cytotoxic lymphocytes. We expect that the proposed studies will provide an expansive understanding of paracrine crosstalk in PDAC and also provide multiple valuable resources and techniques to the PSRC consortium.

抽象的胰腺导管腺癌 (PDAC) 是最致命的恶性肿瘤之一，主要是由于其对当前细胞毒性、靶向和免疫疗法的反应具有广泛的、经测试，促纤维增生基质既抑制血管生成又限制灌注和扩散。通过全身给药治疗药物的输送受到阻碍，降低了药物疗效事实上，PDAC 基质的多种成分支持其生存和生长，例如，通过调节局部免疫抑制的微环境来促进肿瘤存活。离线时，我们之前表明肿瘤基质中至少有一些元素抑制 PDAC 的生长和调制 PDAC 的早期尝试基质以促进药物输送最终在临床转化中失败。证明抑制个体途径后的基质再调节可能导致不可预测的结果对多种其他细胞类型的影响根据这些数据，我们采用了单个旁分泌。通常，通路连接在一起形成“旁分泌级联”，通过多种通路传播我们认为重建这些旁分泌级联提供了更好的机会。了解治疗干预的后果，并推断作用于治疗干预的候选目标 PDAC TME 内广泛的细胞类型来进行基质再调节。为了测试这一点，我们将利用由成员构建的一系列创新系统生物学工具我们的跨学科团队包括一套利用监管计算领域的算法。网络分析，以及用于研究单细胞数据集中结果的技术创新技术。此外，我们将从我们的多学科临床成员收集的样本中获取独特的数据集纽约长老会医院胰腺中心的服务包括获取人类 PDAC。肿瘤间质液并生成匹配组的肿瘤、正常胰腺、脾脏和血液样本我们还将常规地利用新鲜的 PDAC 组织样本来使肿瘤“外植体”成为新的前体。用于 PDAC 短期、中等通量研究的体内模型系统这种新模型系统能够实现以通过研究完整肿瘤或不可能的方式解剖复杂的多细胞表型纯化细胞类型的共培养使用这些方法，我们将重建 PDAC 中的旁分泌级联网络并验证我们还将通过实验来测试通过研究发现的特定候选途径。 Hh 途径将肌成纤维细胞与骨髓源性抑制细胞和细胞毒性淋巴细胞连接起来。我们期望所提出的研究将为 PDAC 中的旁分泌串扰提供更广泛的理解并为PSRC联盟提供多种宝贵的资源和技术。