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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

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.

项目总结