Fibroblasts in the establishment of the liver pre-metastatic niche

成纤维细胞在肝脏转移前生态位的建立中

基本信息

批准号：
10742193
负责人：
Michelle Kayoko Ozaki
金额：
$ 4.92万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10742193
关键词：
3-Dimensional Address Affinity Age Antigen Presentation Breast Cancer Cell Breast Cancer Education Breast Cancer Patient Breast cancer metastasis Cell Separation Cells Childbirth Coculture Techniques Cues Data Data Analyses Deposition Diagnosis Disease Distant Education Environment Equation Extracellular Matrix Fibroblasts Functional disorder Gene Expression Profile Growth Factor Heterogeneity Human Immune Immune System Diseases Immune Tolerance Immunohistochemistry In Vitro Knowledge Laboratory Finding Lactation Liver Liver Fibrosis Malignant Neoplasms Malignant neoplasm of pancreas Mammary Neoplasms Mammary gland Mediating Metastatic Neoplasm to the Liver Modeling Mus Neoplasm Circulating Cells Neoplasm Metastasis Nulliparity Pathologic Patients Phase Platelet-Derived Growth Factor alpha Receptor Population Postpartum Period Pregnancy Primary Neoplasm Process Production Prognosis Proteins Reporting Research Personnel Research Project Grants Research Training Risk Rodent Rodent Model Role Stromal Cells Survival Rate Testing Tissue Expansion Tissues Tumor Promotion Weaning Woman breast cancer diagnosis cancer cell career cell growth cytokine effective therapy human data in vivo insight malignant breast neoplasm neoplastic cell new therapeutic target postpartum breast cancer pregnant prevent reproductive response single-cell RNA sequencing skills standard of care transcriptional reprogramming transcriptome sequencing tumor tumor growth tumor immunology tumor microenvironment tumor progression wound healing young woman

3-Dimensional Address Affinity Age Antigen Presentation Breast Cancer Cell Breast Cancer Education Breast Cancer Patient Breast cancer metastasis Cell Separation Cells Childbirth Coculture Techniques Cues Data Data Analyses Deposition Diagnosis Disease Distant Education Environment Equation Extracellular Matrix Fibroblasts Functional disorder Gene Expression Profile Growth Factor Heterogeneity Human Immune Immune System Diseases Immune Tolerance Immunohistochemistry In Vitro Knowledge Laboratory Finding Lactation Liver Liver Fibrosis Malignant Neoplasms Malignant neoplasm of pancreas Mammary Neoplasms Mammary gland Mediating Metastatic Neoplasm to the Liver Modeling Mus Neoplasm Circulating Cells Neoplasm Metastasis Nulliparity Pathologic Patients Phase Platelet-Derived Growth Factor alpha Receptor Population Postpartum Period Pregnancy Primary Neoplasm Process Production Prognosis Proteins Reporting Research Personnel Research Project Grants Research Training Risk Rodent Rodent Model Role Stromal Cells Survival Rate Testing Tissue Expansion Tissues Tumor Promotion Weaning Woman breast cancer diagnosis cancer cell career cell growth cytokine effective therapy human data in vivo insight malignant breast neoplasm neoplastic cell new therapeutic target postpartum breast cancer pregnant prevent reproductive response single-cell RNA sequencing skills standard of care transcriptional reprogramming transcriptome sequencing tumor tumor growth tumor immunology tumor microenvironment tumor progression wound healing young woman

展开

项目摘要

PROJECT SUMMARY Postpartum breast cancer (PPBC), defined as breast cancer diagnosed within 10 years after a women's last childbirth, accounts for 50% of young women's breast cancer cases. PPBC patients have a 52% 5-year survival rate, whereas age-matched non-PPBC patients have an 80% 5-year survival rate. In rodent studies, supported by patient data, PPBC cases have a greater affinity to progress to overt metastasis after a diagnosis of locally contained disease. Specifically, we find that stage I-III PPBC patients progress to liver metastasis more often than non-PPBC patients. Liver metastasis is a devastating prognosis with only a 3–15-month median survival rate. In rodent models and humans, weaning-induced mammary gland involution has been shown to be a niche that supports establishment of circulating tumor cells in the PPBC patient, and eventual progression to overt metastatic disease. Rodent studies, supported by human studies, show evidence that the liver undergoes remodeling post-weaning, much like the mammary gland. Rodent models of PPBC liver metastasis, support that this remodeling, known as liver involution, establishes a pro-tumor environment, and may account for the increased liver metastasis seen in PPBC patients. This proposal seeks to understand mechanisms by which liver involution supports the liver metastasis niche. Specifically, the proposed aims will explore the role of liver fibroblasts in establishing a unique pre-metastatic niche in the postpartum period during weaning-induced liver involution. While pro-tumor involution fibroblasts have been reported in the mammary gland, it is unknown if liver fibroblasts differentially respond to environmental cues during involution or if they contribute to the establishment of a pro-metastatic niche. Aim 1 will identify and describe distinct populations of fibroblasts across a reproductive cycle using single-cell RNAseq and multiplex immunohistochemistry (mIHC). Liver fibroblast populations will then be functionally tested to investigate if involution liver fibroblasts are tumor promotional. During the K00 phase I will transition into understanding liver fibroblasts in the establishment of liver pre- metastatic niches in breast and pancreatic cancer, with a focus on fibroblast-immune cell-crosstalk. Little is known about how liver fibroblasts respond to tumor education of the pre-metastatic niche. My K00 proposal will investigate if liver fibroblasts alter their antigen presentation to promote immune cell dysfunction over the course of pre-metastatic niche education. This proposal will expand upon my knowledge of liver fibroblasts, and allow me to strength my knowledge of other cancer fields, such as cancer immunology. The research project and training plan proposed in this application will give me the skills and knowledge I need to pursue a career as an independent investigator.

项目摘要产后乳腺癌（PPBC），被定义为妇女后10年内诊断出的乳腺癌最后一个分娩，占年轻女性乳腺癌病例的50％。 PPBC患者的5年52％存活率，而年龄匹配的非PPBC患者的存活率为80％的5年生存率。在啮齿动物研究中，在患者数据的支持下，PPBC病例对诊断后明显转移的进展具有更大的亲和力局部包含的疾病。具体而言，我们发现I-III期PPBC患者发展为肝转移比非PPBC患者更多。肝转移是一种毁灭性的疾病，仅3-15个月中位存活率。在啮齿动物模型和人类中，断奶引起的乳腺相互作用已被证明是支持PPBC患者中循环肿瘤细胞建立的利基市场，最终发展为明显的转移性疾病。在人类研究的支持下，啮齿动物研究表明肝脏进行断奶后进行改造，就像乳腺一样。 PPBC肝的啮齿动物模型转移，支持这种重塑，称为肝脏的反应，建立了一个亲肿瘤的环境，并且可能是PPBC患者中肝转移的增加。该提议试图了解肝脏参与支持肝转移利基市场的机制。具体而言，拟议的目标将探索肝成纤维细胞在产后在产后建立独特的中转移生态位的作用断奶引起的肝脏的涉及。乳腺中已经报道了促肿瘤的成纤维细胞腺体，尚不清楚肝成纤维细胞在互动期间对环境线索有不同的反应有助于建立亲迁移的利基市场。 AIM 1将识别并描述不同的人群使用单细胞RNASEQ和多重免疫组织化学（MIHC）跨生殖循环的成纤维细胞。然后将在功能上测试肝成纤维细胞种群，以研究涉及肝成纤维细胞是否为肿瘤促销。在K00期间乳腺癌和胰腺癌中的转移性壁ni，着重于成纤维细胞 - 免疫细胞刺。几乎没有知道肝成纤维细胞如何应对肿瘤前的肿瘤教育。我的K00提案将研究肝成纤维细胞是否改变其抗原表现以促进免疫细胞功能障碍迁移前的利基教育课程。该建议将扩大我对肝成纤维细胞的了解，并允许我加强对其他癌症领域的了解，例如癌症免疫学。研究本申请中提出的项目和培训计划将为我提供追求的技能和知识作为独立调查员的职业。