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

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。

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.