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Elucidating fibroblast/immune crosstalk and plasticity in pancreatic ductal adenocarcinoma

阐明胰腺导管腺癌中的成纤维细胞/免疫串扰和可塑性

基本信息

批准号：
10531296
负责人：
Jennifer Susan Thalappillil
金额：
$ 0.25万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
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：
2021-12-06 至 2023-02-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10531296
关键词：
3-Dimensional Affect Biology Bone Marrow Cancer Etiology Cancer Survivor Cell Culture Techniques Cells Cessation of life Characteristics Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Data Desmoplastic Development Diagnosis Diphtheria Toxin Disease Disease Progression Engineering Extracellular Matrix Fibroblasts Ganciclovir Genes Genetically Engineered Mouse Goals Heterogeneity Immune Immunosuppression In Vitro Individual Inflammatory Knockout Mice Laboratories Lesion Macrophage Activation Malignant - descriptor Malignant Neoplasms Malignant neoplasm of pancreas Mediating Modeling Morphology Mus Organoids Pancreas Pancreatic Ductal Adenocarcinoma Pancreatic duct Patient-Focused Outcomes Patients Penetration Pharmaceutical Preparations Phenotype Play Population Reporter Role Signal Transduction Smooth Muscle Actin Staining Method Spatial Distribution Stromal Cells Suicide System Testing Therapeutic Time Treatment Efficacy Tumor-associated macrophages United States Work base cancer cell cancer subtypes cell type conditional knockout cytokine ds-DNA effective therapy improved in vivo innovation macrophage men mouse model neoplastic cell novel novel strategies novel therapeutic intervention organoid transplantation pancreatic cancer model pancreatic cancer patients pancreatic neoplasm pancreatic stellate cell promoter survival outcome therapeutic target tumor tumor initiation tumor progression tumorigenesis

项目摘要

Project Summary Pancreatic ductal adenocarcinoma (PDA) is a deadly malignancy, and only 8% of patients diagnosed with this cancer survive 5 years after diagnosis. The poor outcomes of patients with PDA are attributed to the advanced stage of disease at the time of diagnosis and the lack of effective therapies, highlighting the need for new approaches. PDA is characterized by an abundance of extracellular matrix (ECM) around the cancer cells, referred to as a desmoplastic reaction. The desmoplasia provides a niche for different types of stromal cells, including immune cells and cancer-associated fibroblasts (CAFs), which are derived primarily from pancreatic stellate cells (PSCs). PDA CAFs have recently been found to display heterogeneity with distinct phenotypes and spatial distributions: myofibroblastic CAFs (myCAFs) express high levels of α-smooth muscle actin (αSMA) and are in direct physical contact with cancer cells, while inflammatory CAFs (iCAFs) are farther away from tumor cells and secrete inflammatory cytokines. Although this finding has provided opportunities for new therapeutic approaches, their interaction with other cell types within the immunosuppressive, tumor-promoting microenvironment of PDA requires further study. Tumor-associated macrophages (TAMs) are prominent in PDA tumors and are known to have an immunosuppressive function, making them an attractive therapeutic target. However, the mechanisms through which TAMs signal to and impact the biology of iCAFs and myCAFs remains to be explored. This study aims to understand the crosstalk between macrophages and the two CAF subtypes and how these cell populations fluctuate during PDA progression. My preliminary studies show that PSCs promote the proliferation and alternative activation of macrophages in vitro. In addition, in a genetically engineered mouse model (GEMM) of pancreatic cancer, PanIN lesions (precursors of PDA) display an abundance of both αSMA+ fibroblasts and alternatively activated macrophages in close proximity to each other. These results suggest that the fibroblasts and macrophages signal to each other, contributing to the CAF and macrophage phenotypes in PDA. To identify factors responsible for such crosstalk, I will use an innovative, three- dimensional triple co-culture system that combines pancreatic ductal organoids, PSCs, and macrophages. To better understand how the CAF subtypes impact tumor progression and macrophage phenotype in vivo, I will engineer iCAF- and myCAF-conditional knockout mice and perturb each subtype in an orthotopically transplanted organoid mouse model. Ultimately, the identification of iCAF/myCAF and macrophage dynamics and interactions will illuminate the role these cells play in the disease, opening avenues for new and much- needed therapeutic targets.

项目总结