Recurrent enhancer changes accompany the metastatic transition in pancreatic cancer models.
Major finding: Recurrent enhancer changes accompany the metastatic transition in pancreatic cancer models.
Concept: FOXA1 is upregulated during tumor progression and alters enhancer activity to drive metastasis.
Impact: Disrupting enhancer reprogramming with epigenetic therapies may potentially suppress metastasis.
The majority of patients with pancreatic ductal adenocarcinoma (PDAC) have metastatic disease at the time of diagnosis, limiting therapeutic options. However, the molecular mechanisms that underlie metastasis in PDAC are not well understood. The metastatic transition has been linked to disruption of large heterochromatin domains, suggesting a role for chromatin regulation in PDAC metastasis, prompting Roe, Hwang, and colleagues to characterize the enhancer landscape during PDAC progression and metastasis. In paired PDAC organoids derived from primary mouse tumors and metastases, genome-wide profiling revealed regions with increased levels of the active enhancer mark H3K27ac (GAIN regions) and regions with decreased H3K27ac (LOSS regions), although global H3K27ac levels were similar across the samples. The H3K27ac GAIN and LOSS regions were consistent across the metastatic samples, indicating that recurrent changes in H3K27ac accompany the metastatic transition. The large majority of GAIN and LOSS regions occurred in enhancers, and GAIN enhancers exhibited enrichment of H3K4me1 in metastatic organoids without changes in chromatin accessibility. The transcription factor FOXA1 was upregulated during PDAC progression and was enriched at GAIN regions where it promoted enhancer activation. FOXA1 expression increased anchorage-independent growth and invasion in pancreatic cancer cells and promoted metastasis in vivo. FOXA1 cooperated with GATA5 to activate GAIN enhancers, and, in vivo, FOXA1- and GATA5-expressing tumors grew more rapidly and developed more frequent metastases. In contrast, FOXA1 depletion deactivated GAIN enhancers in PDAC organoids and resulted in fewer mice developing metastasis in vivo. Together, these findings demonstrate that FOXA1 directs enhancer reprogramming to promote PDAC progression and metastasis, suggesting the possibility for epigenetic drugs to target metastasis in patients with PDAC.
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