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) 的特点是缺氧、营养不良。缺乏免疫抑制的肿瘤微环境（TME）和可能损害治疗的纤维化基质回复。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有助于深入了解 PDAC 的进展和治疗抵抗。特别是，癌症相关成纤维细胞 (CAF) 是 TME 的主要非免疫细胞成分，并且是由几种不同的亚型组成，这些亚型根据肿瘤亚型和周围环境而变化微环境生态位。在这个提案中，我们聚集了一个由基础和翻译组成的多学科团队研究人员将在我们之前的研究基础上重点研究肿瘤-TME 共同组织者模型探究 TME 中 PDAC 肿瘤细胞和 CAF 之间的相互作用。具体来说，我们将检查肿瘤细胞和 CAF 之间的相互信号传导塑造恶性细胞和 CAF 的总体假设以特定环境的方式显示表型，可以通过先前的治疗和器官特异性生态位进行调节。我们将利用多种内置功能，包括基因工程小鼠模型 (GEMM)、患者模型衍生类器官（PDO）和匹配的成纤维细胞模型、功能遗传筛选和系列临床试验活检以研究 PDAC TME 疾病进展和治疗耐药性的连续体。具体来说，我们建议 (1) 确定靶向器官特异性 PDAC-CAF 相互作用是否增强治疗反应，(2) 询问 PDAC 期间肿瘤细胞和 CAF 重编程产生的新漏洞 (3) 研究 TGFB 阻断是否会破坏肿瘤细胞-CAF 串扰并使 PDAC 对化疗。在进行这些研究的过程中，我们将与 PDAC 基质重编程的其他成员合作联盟 (PSRC) 开展合作研究，以了解 PDAC 和 TME 交互计划的方式肿瘤进展和治疗反应。