Abstract IA019: How to target lung metastasis: dynamic changes in chromatin accessibility during osteosarcoma lung metastasis expose vulnerabilities

Abstract

Abstract The metastatic cascade describes the series of steps required for a cancer cell to successfully spread from its primary tumor to a secondary organ. Despite knowing that metastasis is a fluid process, almost all studies to date have relied on end-point assays. As a result, little is known about the continuum of molecular events required for successful growth within the secondary organ. By profiling accessible chromatin in osteosarcoma cells grown in vitro and isolated from an early and late timepoint during lung metastasis, we identify temporally distinct epigenomic reprogramming events that occur as tumors form and grow within the metastatic microenvironment. Furthermore, these data pinpoint key upstream transcription factors responsible for the dynamic chromatin changes. Through paired in vivo and in vitro CRISPR drop-out screens, we show a subset of these putative pro-metastatic transcription factors are essential for lung metastasis, but dispensable for in vitro growth. Targeting the same factors with chemical probes in vitro and ex vivo demonstrated similar context-dependent essentiality. Altogether, our study demonstrates the epigenomes of metastasizing cancer cells are tightly regulated in a dynamic and context-specific manner, and the transcription factors controlling this process may serve as novel vulnerabilities. Citation Format: Peter C. Scacheri. How to target lung metastasis: dynamic changes in chromatin accessibility during osteosarcoma lung metastasis expose vulnerabilities [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr IA019.