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.

项目总结/摘要 胰腺导管腺癌（PDAC）是五种最致命的癌症之一，由于缺乏有效的治疗方法， 治疗方案。PDAC的一个标志是癌症相关成纤维细胞（CAF）的扩增。CAFs播放 在PDAC微环境中起关键和复杂的作用，以调节肿瘤进展和治疗反应。 我的研究计划的长期目标是确定细胞的起源，异质性和功能， 胰腺癌中的CAF为了确定PDAC中CAFs的组织来源，我进行了谱系追踪 使用基因工程小鼠模型进行实验。内脏间充质是一种特殊类型的 在胎儿发育过程中与胰腺上皮相邻的间充质。我的研究表明， 内脏间充质是PDAC中CAF的胎儿起源（Han等，Nat Commun，出版中）。在当前的 我的目标是进一步研究内脏来源的CAFs是否保持某些分子特征， 他们的胎儿祖先Hedgehog通路是上皮细胞和巨噬细胞之间的关键旁分泌信号。 在胎儿发育期间，间充质被激活，并在胰腺肿瘤发生期间被重新激活。刺猬 信号调节PDAC进展，但其在CAF中的下游靶点尚未确定。我在研究 研究表明转录因子FOXF 1和GATA 6是Hedgehog通路的下游靶点 在胎儿内脏间充质中。我的初步研究表明，这些因素也表现在 PDAC CAF在肿瘤微环境中以区域性不同的模式存在。在目标1中，我将确定 FOXF 1/GATA 6在CAFs中的模式化受Hedgehog途径活性调节。Hedgehog激动剂或 拮抗剂将用于体外细胞或类器官培养和体内小鼠模型。在目标2中，我将确定 FOXF 1 + CAFs和GATA 6 + CAFs在PDAC中的功能， 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， 在PDAC CAF生物学中，包括由胎儿特征的选择性持续性定义的新型细胞异质性 与上皮协调，某些胎儿特征在非细胞肿瘤中发挥肿瘤抑制作用， 自主的方式。最终，肿瘤微环境中的这些知识可以揭示关键靶点， 抑制肿瘤进展和延长PDAC患者存活的治疗途径。我接受了严格的训练 在发育生物学上的研究四年前，我开始接受癌症生物学的培训， 霍林斯癌症中心的博士后在K99阶段，我的目标是进一步提高我的专业知识 在胰腺癌的研究，并获得一些额外的技能，这是必不可少的启动我的 R 00阶段的独立研究计划。我渴望从胚胎学和 肿瘤学发展新的观点和解决基本的生物学问题。