Tumor progression and chromatin landscape of lung cancer are regulated by the lineage factor GATA6

Abstract

Lineage selective transcription factors (TFs) are important regulators of tumorigenesis, but their biological functions are often context dependent with undefined epigenetic mechanisms of action. In this study, we uncover a conditional role for the endodermal and pulmonary specifying TF GATA6 in lung adenocarcinoma (LUAD) progression. Impairing Gata6 in genetically engineered mouse models reduces the proliferation and increases the differentiation of Kras mutant LUAD tumors. These effects are influenced by the epithelial cell type that is targeted for transformation and genetic context of Krasmediated tumor initiation. In LUAD cells derived from surfactant protein C expressing progenitors, we identify multiple genomic loci that are bound by GATA6. Moreover, suppression of Gata6 in these cells significantly alters chromatin accessibility, particularly at distal enhancer elements. Analogous to its paradoxical activity in lung development, GATA6 expression fluctuates during different stages of LUAD progression and can epigenetically control diverse transcriptional programs associated with bone morphogenetic protein signaling, alveolar specification, and tumor suppression. These findings reveal how GATA6 can modulate the chromatin landscape of lung cancer cells to control their proliferation and divergent lineage dependencies during tumor progression.

Lineage tracing reveals the phylodynamics, plasticity, and paths of tumor evolution

“…Integration of phylodynamics and transcriptome uncovers fitness-associated gene programs for KP tumors With quantitative measurements of single-cell fitness in each tumor, we next sought to identify the molecular features consistently associated with subclonal expansions. Consistent with KP tumor progression being driven largely by epigenetic rather than genetic changes (LaFave et al, 2020;Arnal-Estape ´et al, 2020;Marjanovic et al, 2020), we observed that CNV profiles within expansions were largely inconsistent across tumors (Figure S2L). We therefore examined the transcriptomic differences underpinning expansion.…”

RETRACTED ARTICLE: Long non-coding RNA GATA6-AS1 upregulates GATA6 to regulate the biological behaviors of lung adenocarcinoma cells

“…revealed that silencing of GATA6 exerts anti-oncogenic effects in LUAD [ 46 ]. Inhibition of GATA6 reduces the proliferation of Kras mutant LUAD tumors in mouse models [ 47 ]. GATA6 activates PCAT1 to maintain stemness of non-small cell lung cancer cells [ 48 ].…”

Lineage Recording Reveals the Phylodynamics, Plasticity and Paths of Tumor Evolution

“…With quantitative measurements of single-cell fitness in each tumor, we next sought to identify the molecular features consistently associated with subclonal expansions. Consistent with KP tumors having low mutational burden and progression mainly utilizing epigenetic changes as major drivers (Arnal-Estapé et al, 2020;LaFave et al, 2020), CNV profiles within expansions were largely inconsistent across tumors and thus unlikely to be the only driver of tumor expansion (Fig S2L). We therefore examined the transcriptomic differences underpinning expansion.…”