Stromal modulation of pancreatic cancer malignant cell state and therapeutic sensitivity

胰腺癌恶性细胞状态的基质调节和治疗敏感性

基本信息

批准号：
10517569
负责人：
Andrew James Aguirre
金额：
$ 103.7万
依托单位：
DANA-FARBER CANCER INST
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：
2022-09-19 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10517569
关键词：
Affect Aftercare Antibodies Archives Biology Biopsy Cell Nucleus Cells Cellular Structures Clinical Clinical Trials Coculture Techniques Complex Data Dermal Disease Progression Disease Resistance Evolution Exhibits Fibroblasts Gene Expression Genetic Screening Genetically Engineered Mouse Genomic approach Growth Factor Heterogeneity Human Hypoxia Immunofluorescence Immunologic Impairment Investigation Isogenic transplantation Ligands Light Liver Malignant Neoplasms Malignant neoplasm of pancreas Mesenchymal Metastatic Neoplasm to the Liver Modeling Nature Neoadjuvant Therapy Neoplasm Metastasis Nutrient Organ Organoids Pancreatic Ductal Adenocarcinoma Patients Pattern Pericytes Pharmaceutical Preparations Phenotype Play Population Prior Therapy Process Proteins Resistance Role Sampling Shapes Signal Transduction Small Nuclear RNA Specimen Stromal Cells TGFB1 gene Testing Therapeutic Tumor Subtype Work base biobank cancer cell cell type chemotherapy cytokine differential expression digital functional genomics innovation insight member multidisciplinary neoplastic cell novel novel strategies novel therapeutic intervention programs response single-cell RNA sequencing standard of care therapeutic target therapy resistant transcriptome transcriptome sequencing translational scientist transplant model treatment response tumor tumor microenvironment tumor progression tumor-immune system interactions

项目摘要

Abstract Unlike many cancers, pancreatic ductal adenocarcinoma (PDAC) is characterized by a hypoxic, nutrient- deprived, immunosuppressive tumor microenvironment (TME) and a fibrotic stroma that may impair treatment response. Recent single-cell studies suggest a complex interplay between malignant tumor cells and other cell types within the TME, with crosstalk between tumor and stromal cell types influencing malignant cell phenotypes, including responses to therapy. Understanding these interactions will provide insight into PDAC progression and therapy resistance. In particular, cancer-associated fibroblasts (CAFs) are a major non-immune cell component of the TME and are comprised of several distinct subtypes that vary based on tumor subtype and the surrounding microenvironmental niche. In this proposal, we bring together a multidisciplinary team of basic and translational investigators that will build upon our prior studies to investigate the Tumor-TME co-organizer model with a focus on interrogating interactions between PDAC tumor cells and CAFs in the TME. Specifically, we will examine the overarching hypothesis that reciprocal signaling between tumor cells and CAFs shapes malignant cell and CAF phenotypes in a context-specific manner that can be modulated by prior therapy and the organ-specific niche. We will leverage multiple built-in capabilities, including genetically engineered mouse models (GEMMs), patient- derived organoid (PDO) and matched fibroblast models, functional genetic screens and clinical trials with serial biopsies to study the PDAC TME continuum in disease progression and resistance to therapy. Specifically, we propose (1) to determine whether targeting organ-specific PDAC-CAF interactions enhances therapeutic responses, (2) to interrogate novel vulnerabilities resulting from tumor cell and CAF reprogramming during PDAC therapy, and (3) investigate whether TGFB blockade disrupts tumor cell-CAF crosstalk and sensitizes PDAC to chemotherapy. In pursuing these studies, we will work with other members of the PDAC Stromal Reprogramming Consortium (PSRC) to pursue collaborative studies to understand how PDAC and TME interactions program tumor progression and therapy responses.

抽象的与许多癌症不同，胰腺导管腺癌（PDAC）的特征是低氧，营养 - 被剥夺的免疫抑制肿瘤微环境（TME）和可能损害治疗的纤维基质回复。最近的单细胞研究表明，恶性肿瘤细胞与其他细胞之间存在复杂的相互作用 TME内的类型，肿瘤和基质细胞类型之间的串扰，影响恶性细胞表型，包括对治疗的反应。了解这些相互作用将为PDAC进展和治疗抗性。特别是，与癌症相关的成纤维细胞（CAF）是TME的主要非免疫细胞成分，并且是由几种基于肿瘤亚型和周围的不同亚型组成微环境利基市场。在此提案中，我们将基本和翻译的多学科团队汇总在一起研究人员将以我们先前的研究为基础，以研究肿瘤-TME共同组织者模型的重点关于质疑PDAC肿瘤细胞与TME中CAF之间的相互作用。具体来说，我们将研究总体假设，即肿瘤细胞和CAF之间的相互信号传导塑造恶性细胞和CAF 表型以特定于上下文的方式可以通过先前的治疗和特定器官特异性利基来调节。我们将利用多种内置功能，包括基因工程的小鼠模型（GEMM），患者 - 衍生的类器官（PDO）和匹配的成纤维细胞模型，功能性遗传筛选和临床试验活检以研究疾病进展和对治疗抗性的PDAC TME连续体。具体来说，我们提议（1）确定靶向器官特异性PDAC-CAF相互作用是否增强了治疗响应，（2）审查PDAC期间肿瘤细胞和CAF重新编程产生的新漏洞和（3）研究TGFB是否会破坏肿瘤细胞-CAF串扰并使PDAC敏感化学疗法。在进行这些研究时，我们将与PDAC基质重新编程的其他成员合作财团（PSRC）进行协作研究，以了解PDAC和TME互动计划如何肿瘤进展和治疗反应。