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Acquired anoikis resistance mediates enhancer-driven subtype plasticity in pancreatic cancer [RNA-seq]

ABSTRACT: Genetic aberrations, including mutations or deletions in KRAS, TP53, SMAD4, and CDKN2A, are common causes of pancreatic ductal adenocarcinoma (PDA). Recent large-scale transcriptomic studies demonstrated that heterogeneous gene expressions played an essential role in determining molecular subtypes of PDA, although it remains unclear what the biological cues and consequences of distinct transcriptional programs are. Here, we describe an anoikis-induction-based experimental model that enforces the transition toward a squamous subtype of PDA cells. Characteristics of the squamous subtype, represented by aggressive behaviors, are faithfully recapitulated in vitro and in vivo, demonstrating the physiological relevance of this model. Integrated analysis of epigenome and transcriptome reveals that squamous subtype PDA cells acquire pro-angiogenic enhancer activity of which is sustained by the transcription factor TEAD2. Genetic and pharmacological inhibition of TEAD2 of these tumor cells impairs their pro-angiogenic phenotypes in vitro and cancer progression in vivo. Furthermore, we found that CD109 is a critical TEAD2 target that retains activated JAK-STAT signaling. Together, our findings implicate a TEAD2-CD109-JAK/STAT axis as a potential therapeutic vulnerability concealed in the squamous subtype-associated epigenome of pancreatic cancer cells.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE202532 | GEO | 2023/04/04

REPOSITORIES: GEO

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Acquired anoikis resistance mediates enhancer-driven subtype plasticity in pancreatic cancer [ChIP-Seq]

Project description:Genetic aberrations, including mutations or deletions in KRAS, TP53, SMAD4, and CDKN2A, are common causes of pancreatic ductal adenocarcinoma (PDA). Recent large-scale transcriptomic studies demonstrated that heterogeneous gene expressions played an essential role in determining molecular subtypes of PDA, although it remains unclear what the biological cues and consequences of distinct transcriptional programs are. Here, we describe an anoikis-induction-based experimental model that enforces the transition toward a squamous subtype of PDA cells. Characteristics of the squamous subtype, represented by aggressive behaviors, are faithfully recapitulated in vitro and in vivo, demonstrating the physiological relevance of this model. Integrated analysis of epigenome and transcriptome reveals that squamous subtype PDA cells acquire pro-angiogenic enhancer activity of which is sustained by the transcription factor TEAD2. Genetic and pharmacological inhibition of TEAD2 of these tumor cells impairs their pro-angiogenic phenotypes in vitro and cancer progression in vivo. Furthermore, we found that CD109 is a critical TEAD2 target that retains activated JAK-STAT signaling. Together, our findings implicate a TEAD2-CD109-JAK/STAT axis as a potential therapeutic vulnerability concealed in the squamous subtype-associated epigenome of pancreatic cancer cells.

2023-04-04 | GSE202527 | GEO

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