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.