GSE167381
LKB1 inactivation initiates a chromatin remodeling cascade to drive metastatic progression
Metastasis is the leading cause of cancer-related deaths, enabling cancer cells to expand to secondary tumor sites and compromise systemic organ function1. Given that primary tumors and metastases often share the same constellation of functional driver mutations2–4, the mechanisms driving their distinct phenotypes are unclear. Here, we show that inactivation of a frequently mutated tumor suppressor gene, liver kinase B1 (LKB1), has evolving effects throughout lung cancer progression, differentially re-programming the epigenetic landscape of early-stage primary tumors compared to late-stage metastases. By integrating genome-scale CRISPR/Cas9 screening with bulk and single-cell multi-omic analyses, we unexpectedly identify LKB1 as a master regulator of chromatin state in lung adenocarcinoma primary tumors. Using an in vivo model of metastatic progression, we further reveal that loss of LKB1 activates the early endoderm transcription factor SOX17 in metastases and metastatic-like sub-populations of cancer cells within primary tumors. SOX17 expression is both necessary and sufficient to drive a second wave of epigenetic changes in LKB1-deficient cells that enhances metastatic ability. Overall, our study demonstrates how the downstream effects of an individual driver mutation can change throughout cancer development, with implications for stage-specific therapeutic resistance mechanisms and the gene regulatory underpinnings of metastatic evolution. Overall design: Bulk ATAC-seq and bulk RNA-seq was performed on immortalized cell lines and murine lung adenocarcinoma primary tumors and metastases following gene perturbations and/or different treatment conditions. Single-cell ATAC-seq was performed on murine lung adenocarcinoma primary tumors of different genotypes. Genome-wide CRISPR screen was performed on immortalized cell lines of two different genotypes.