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

• 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
• 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

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），定义为女性产后10年内诊断出的乳腺癌。 最后一次分娩，占年轻女性乳腺癌病例的50%。PPBC患者有52%的5年 年龄匹配的非PPBC患者的5年生存率为80%。在啮齿动物研究中， 根据患者数据，PPBC病例在诊断后更容易进展为明显的转移 局部控制的疾病。具体来说，我们发现I-III期PPBC患者进展为肝转移， 比非PPBC患者更常见。肝转移是一个毁灭性的预后，只有3-15个月 平均存活率在啮齿类动物模型和人类中，断奶诱导的乳腺退化已经被证实， 显示为支持在PPBC患者中建立循环肿瘤细胞的小生境，并且最终 进展为明显的转移性疾病。啮齿类动物的研究得到了人类研究的支持， 肝脏在断奶后经历重塑，很像乳腺。PPBC肝的啮齿动物模型 转移，支持这种重塑，称为肝脏退化，建立了促肿瘤环境， 可能是PPBC患者肝转移增加的原因。这一建议旨在了解 肝退化支持肝转移小生境的机制。具体而言，拟议目标将 探索肝成纤维细胞在产后期间建立独特的转移前生态位中的作用， 断奶诱导的肝脏退化。虽然已报道乳腺癌中的促肿瘤退化成纤维细胞 腺体，这是未知的，如果肝成纤维细胞差异反应的环境线索，在退化或如果他们 有助于建立促转移的生态位。目标1将确定和描述不同的人口， 使用单细胞RNAseq和多重免疫组织化学（mIHC）检测整个生殖周期的成纤维细胞。 然后对肝成纤维细胞群进行功能测试，以研究退化肝成纤维细胞是否是肿瘤细胞。 促销。 在K 00阶段，我将过渡到了解肝成纤维细胞在建立肝前病变中的作用。 乳腺癌和胰腺癌的转移小生境，重点是成纤维细胞-免疫细胞-串扰。之甚少 了解肝成纤维细胞如何对转移前小生境的肿瘤教育做出反应。我的K 00提案将 研究肝成纤维细胞是否改变其抗原呈递以促进免疫细胞功能障碍， 转移前的利基教育课程。这个建议将扩大我对肝成纤维细胞的了解， 并让我加强我在其他癌症领域的知识，如癌症免疫学。研究 在此申请中提出的项目和培训计划将为我提供所需的技能和知识， 作为一名独立调查员。