Origin, diversification and function of pancreatic cancer associated fibroblasts

胰腺癌相关成纤维细胞的起源、多样化和功能

• 批准号: 10739919
• 负责人: Lu Han
• 金额: $ 13.11万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739919
• 关键词: Acceleration; Adult; Agonist; Alleles; Biological; Biology; Bone Marrow Cells; Cancer Biology; Cancer Center; Cells; Characteristics; Coculture Techniques; Complex; Correlation Studies; Data; Developmental Biology; Diagnosis; Disease; Embryology; Endoderm; Epithelial Cells; Epithelium; Erinaceidae; FOXF1 gene; Fetal Development; Fibroblasts; Future; Gene Deletion; Gene Expression; Gene Expression Profile; Genetic; Genetically Engineered Mouse; Heterogeneity; Human; Immune; In Vitro; KRASG12D; Knowledge; Ligands; Light; Malignant Neoplasms; Malignant neoplasm of pancreas; Mesenchymal; Mesenchyme; Modeling; Molecular; Molecular Profiling; Mus; Oncology; Organ; Organoids; Pancreas; Pancreatic Ductal Adenocarcinoma; Paracrine Communication; Pathogenesis; Pathway interactions; Patients; Pattern; Phase; Physiology; Play; Postdoctoral Fellow; Regulation; Research; Role; Sampling; Testing; Therapeutic; Tissues; Training; Tumor Burden; Tumor-Derived; antagonist; anticancer research; cancer subtypes; cancer type; conditional knockout; design; effective therapy; experimental study; fetal; in vivo; insight; mouse model; neoplastic cell; novel; pancreatic tumorigenesis; progenitor; programs; restraint; skills; smoothened signaling pathway; stem; success; targeted treatment; therapeutically effective; transcription factor; treatment response; treatment strategy; tumor; tumor microenvironment; tumor progression

Project Summary/Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the top five deadliest cancers due to a lack of effective treatment options. One hallmark of PDAC is the expansion of cancer associated fibroblasts (CAFs). CAFs play critical and complex roles in PDAC microenvironment to modulate tumor progression and therapeutic response. The long-term objective of my research program is to determine the cellular origin, heterogeneity and function of CAFs in pancreatic cancer. To identify the tissue origin of CAFs in PDAC, I performed lineage tracing experiments using genetically engineered mouse models. The splanchnic mesenchyme is a particular type of mesenchyme adjacent to the pancreatic epithelium during fetal development. My studies demonstrated that the splanchnic mesenchyme is the fetal origin of CAFs in PDAC (Han et al, Nat Commun, in press). In this current proposal, I aim to further investigate whether splanchnic-derived CAFs maintain certain molecular signatures of their fetal progenitors. The Hedgehog pathway is a critical paracrine signal between the epithelium and mesenchyme during fetal development and is reactivated during tumorigenesis of the pancreas. The Hedgehog signal modulates PDAC progression, but its downstream targets in CAFs have not been identified. My graduate study showed that transcription factors FOXF1 and GATA6 are downstream targets of the Hedgehog pathway in the fetal splanchnic mesenchyme. My preliminary studies suggested that these factors are also expressed in PDAC CAFs in a regionally distinct pattern within the tumor microenvironment. In Aim 1, I will determine whether FOXF1/GATA6 patterning in CAFs is regulated by the Hedgehog pathway activity. Hedgehog agonist or antagonist will be utilized in in vitro cell or organoid culture and in vivo mouse models. In Aim 2, I will determine the function of FOXF1+ CAFs and GATA6+ CAFs in PDAC by deleting these genes specifically in CAFs both in vitro and in vivo as well as in patient correlation studies. The completion of this study will provide critical insights in PDAC CAF biology, including novel cellular heterogeneity defined by selective persistence of fetal signatures in coordination with the epithelium, and certain fetal signatures playing tumor-suppressing roles in a non-cell autonomous manner. Ultimately, such knowledge in tumor microenvironment may reveal critical targets and therapeutic avenues to inhibit tumor progression and prolong PDAC patient survival. I received rigorous training in developmental biology during my graduate study. Four years ago, I started my training in cancer biology as a postdoctoral fellow in the Hollings Cancer Center. During the K99 phase, I aim to further enhance my expertise in pancreatic cancer research and to acquire several additional skills, which are essential to launch my independent research program during the R00 phase. I aspire to draw from paradigms in both embryology and oncology to develop novel perspectives and to tackle fundamental biological questions.

项目概要/摘要 由于缺乏有效的治疗方法，胰腺导管腺癌（PDAC）是最致命的五种癌症之一。 治疗方案。 PDAC 的标志之一是癌症相关成纤维细胞 (CAF) 的扩增。 CAF 比赛 PDAC 微环境在调节肿瘤进展和治疗反应方面发挥着关键而复杂的作用。 我的研究计划的长期目标是确定细胞起源、异质性和功能 胰腺癌中的 CAF。为了确定 PDAC 中 CAF 的组织起源，我进行了谱系追踪 使用基因工程小鼠模型进行的实验。内脏间充质是一种特殊类型 胎儿发育过程中与胰腺上皮相邻的间质。我的研究表明 内脏间充质是 PDAC 中 CAF 的胎儿起源（Han 等人，Nat Commun，出版中）。在当前这个 建议，我的目的是进一步研究内脏衍生的 CAF 是否保持某些分子特征 他们的胎儿祖先。 Hedgehog 通路是上皮细胞和上皮细胞之间的重要旁分泌信号。 间充质在胎儿发育期间产生，并在胰腺肿瘤发生期间重新激活。刺猬 信号调节 PDAC 进展，但其在 CAF 中的下游靶点尚未确定。我的毕业生 研究表明转录因子 FOXF1 和 GATA6 是 Hedgehog 通路的下游靶标 存在于胎儿内脏间质中。我的初步研究表明这些因素也表现在 PDAC CAF 在肿瘤微环境中具有区域独特的模式。在目标 1 中，我将确定是否 CAF 中的 FOXF1/GATA6 模式受 Hedgehog 通路活性调节。 Hedgehog激动剂或 拮抗剂将用于体外细胞或类器官培养以及体内小鼠模型。在目标 2 中，我将确定 通过在 PDAC 中特异删除 CAF 中的这些基因来研究 FOXF1+ CAF 和 GATA6+ CAF 的功能 体外和体内以及患者相关性研究。这项研究的完成将提供重要的见解 PDAC CAF 生物学，包括由胎儿特征的选择性持久性定义的新型细胞异质性 与上皮细胞协调，某些胎儿特征在非细胞中发挥肿瘤抑制作用 自主方式。最终，肿瘤微环境中的此类知识可能会揭示关键靶点和 抑制肿瘤进展并延长 PDAC 患者生存期的治疗途径。我接受了严格的训练 在我研究生学习期间研究发育生物学。四年前，我开始接受癌症生物学培训 霍林斯癌症中心博士后研究员。在K99阶段，我的目标是进一步提升我的专业知识 从事胰腺癌研究并获得一些额外的技能，这些技能对于开展我的研究至关重要 R00阶段的独立研究计划。我渴望借鉴胚胎学和 肿瘤学发展新的视角并解决基本的生物学问题。