Targeting ERK-AKT-mediated single-cell drug response heterogeneity in metastatic osteosarcoma

针对转移性骨肉瘤中 ERK-AKT 介导的单细胞药物反应异质性

• 批准号: 10896845
• 负责人: Alexander E Davies
• 金额: $ 11.97万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-05 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10896845
• 关键词: ABCB1 gene; ABCC1 gene; ABCG2 gene; AKT Signaling Pathway; Address; American Cancer Society; Antineoplastic Agents; BCL2 gene; Brain; Breast Cancer Cell; Cause of Death; Cell Fraction; Cell Proliferation; Cell physiology; Cells; Childhood Osteosarcoma; Cisplatin; Collaborations; Cues; Data; Development; Diagnosis; Disease; Doxorubicin; Drops; Drug Modulation; Drug Targeting; Drug resistance; Drug usage; Exhibits; Extracellular Signal Regulated Kinases; FOS gene; Gene Expression; Genes; Goals; Heterogeneity; Imaging Techniques; Immediate-Early Genes; Individual; Invaded; Lesion; Ligands; Link; Liver; Lung; MCL1 gene; Malignant Neoplasms; Mediating; Mentors; Metastatic Neoplasm to the Lung; Metastatic Osteosarcoma; Modeling; Multidrug Resistance Gene; Neoplasm Metastasis; Outcome; Paracrine Communication; Pathway interactions; Patient-Focused Outcomes; Patients; Persons; Pharmaceutical Preparations; Phenotype; Physiologic pulse; Postdoctoral Fellow; Primary Neoplasm; Process; Proto-Oncogene Proteins c-akt; Receptor Protein-Tyrosine Kinases; Research; Resistance; Sampling; Signal Induction; Signal Pathway; Signal Transduction; Site; Solid Neoplasm; Survival Rate; Techniques; Testing; Time; Transforming Growth Factors; Translating; Treatment Efficacy; Tumor Biology; Up-Regulation; Work; aged; behavior influence; bone; cancer cell; career; comparative; cytotoxic; drug sensitivity; drug-sensitive; extracellular; high resolution imaging; improved; live cell imaging; malignant breast neoplasm; mortality; neoplastic cell; non-genetic; novel strategies; osteosarcoma; paracrine; pharmacologic; programs; response; screening; skills; targeted treatment; transcriptome sequencing; treatment response; tumor; tumor microenvironment

PROJECT SUMMARY/ ABSTRACT Cellular plasticity, the ability of cells to bi-directionally transition between states over time, provides a non- genetic mechanism for cells to sample different phenotypes, spontaneously, or in response to cues from the microenvironment. In the context of cancer drug response, plasticity is problematic because it allows cancer cells to transition between drug resistant and sensitive states over time. While this phenomenon is well documented in primary tumors it appears to be a substantial problem in the metastatic microenvironment where cancer cells often exhibit profound drug resistance leading to patient mortality. In the proposed work, we aim to address this problem to determine how signals arising from the metastatic microenvironment of the lung regulate drug response plasticity and how we can inhibit phenotypic transitions from drug sensitive to resistant states in single cells. Additionally, completion of the aims proposed in this K01 submission will facilitate development of a research program that is distinct from my post-doctoral mentors, sharpen my research skills, and set the stage for a successful independent career using live-cell imaging techniques to study metastatic tumor biology and drug resistance.

项目摘要/摘要 细胞可塑性，即细胞随时间在状态之间双向转换的能力，提供了一种非 细胞自发采样不同表型的遗传机制，或对来自 微环境。在抗癌药物反应的背景下，可塑性是有问题的，因为它允许癌细胞 随着时间的推移在耐药和敏感状态之间转换。虽然这种现象有很好的记录 在原发肿瘤中，癌细胞在转移的微环境中似乎是一个实质性的问题 经常表现出严重的耐药性，导致患者死亡。在拟议的工作中，我们的目标是解决这个问题 确定来自肺转移微环境的信号如何调节药物的问题 反应可塑性和我们如何抑制从药物敏感状态到耐药状态的表型转变 细胞。此外，完成本K01意见书中建议的目标将有助于制定 有别于我的博士后导师的研究计划，磨练我的研究技能，为我的研究奠定基础 使用活细胞成像技术研究转移性肿瘤生物学和 抗药性。