Origin, diversification and function of pancreatic cancer associated fibroblasts

项目摘要/摘要 摘要胰腺导管腺癌是五大死亡率最高的癌症之一，因缺乏有效的治疗方法。 治疗方案。PDAC的一个特征是肿瘤相关成纤维细胞(CAF)的扩张。CAFS比赛 在PDAC微环境中调节肿瘤进展和治疗反应的关键和复杂的作用。 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 CAFS在胰腺癌中的应用为了确定PDAC中CAF的组织起源，我进行了血统追踪 使用基因工程小鼠模型的实验。内脏间充质是一种特殊类型的 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的胎儿来源(han等，NAT Commun，正在出版中)。在这股洋流中 建议，我的目标是进一步调查内脏来源的CAF是否保持了某些分子特征 他们的胎儿祖先。Hedgehog通路是上皮细胞和Hedgehog细胞之间的关键旁分泌信号 间充质细胞在胎儿发育过程中被激活，在胰腺肿瘤形成过程中被重新激活。刺猬 信号调节PDAC的进程，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途径的下游靶标 在胎儿内脏间充质中。我的初步研究表明，这些因素也在 在肿瘤微环境中，PDAC CAF在区域上是不同的。在目标1中，我将确定是否 CAF中FOXF1/GATA6模式的形成受Hedgehog途径活性的调节。刺猬激动剂或 拮抗剂将用于体外细胞或器官培养和体内小鼠模型。在目标2中，我将决定 FOXF1+CAF和GATA6+CAF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定义的新的细胞异质性 与上皮细胞协调，以及某些胎儿信号在非细胞中发挥抑制肿瘤的作用 自主的方式。最终，肿瘤微环境中的这种知识可能会揭示关键靶点和 抑制肿瘤进展和延长PDAC患者生存的治疗途径。我接受了严格的训练 在我研究生学习期间，我学习了发育生物学。四年前，我开始接受癌症生物学方面的培训 霍林斯癌症中心的博士后研究员。在K99阶段，我的目标是进一步提高我的专业知识 在胰腺癌研究方面，并获得几项额外的技能，这些技能对于启动我的 R00阶段的独立研究计划。我渴望从胚胎学和 肿瘤学，以开发新的视角和解决基本的生物学问题。

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.