[초청강연] TEAD2 mediates angiogenic transcriptional programs to the squamous subtype identity in pancreatic ductal adenocarcinoma

TEAD2 mediates angiogenic transcriptional programs to the
squamous subtype identity in pancreatic ductal adenocarcinoma

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 consequences of distinct
transcriptional programs are. Here, we describe an experimental platform 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. Furthermore, integrated analysis of epigenome and transcriptome reveals
that squamous subtype PDA cells acquire pro-angiogenic enhancer activity of which
is sustained by the Hippo pathway 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. This study
establishes tumor angiogenesis as a potential therapeutic vulnerability concealed in
the squamous subtype of pancreatic cancer.