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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/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地或响应来自外部环境的提示对不同表型进行采样的遗传机制微环境。在癌症药物反应的背景下，可塑性是有问题的，因为它允许癌细胞随着时间的推移，在耐药状态和敏感状态之间转变。虽然这种现象有据可查在原发性肿瘤中，癌细胞所在的转移性微环境似乎是一个重大问题通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肺部转移微环境产生的信号如何调节药物的问题反应可塑性以及我们如何抑制从药物敏感到耐药状态的表型转变细胞。此外，完成本 K01 提交文件中提出的目标将有助于开发与我的博士后导师不同的研究计划，提高了我的研究技能，并奠定了基础使用活细胞成像技术研究转移性肿瘤生物学并取得成功的独立职业生涯耐药性。