Reciprocal regulation of pancreatic ductal adenocarcinoma growth and molecular subtype by HNF4α and SIX1/4.

Objective: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a 5-year survival of less than 5%. Transcriptomic analysis has identified two clinically relevant molecular subtypes of PDAC: classical and basal-like. The classical subtype is characterised by a more favourable prognosis and better response to chemotherapy than the basal-like subtype.

The role of lineage specifiers in pancreatic ductal adenocarcinoma.

Over the last decade, multiple genomics studies have led to the identification of discrete molecular subtypes of pancreatic ductal adenocarcinoma. A general theme has emerged that most pancreatic ductal adenocarcinoma (PDAC) can be grouped into two major subtypes based on cancer cell autonomous properties: classical/pancreatic progenitor and basal-like/squamous. The classical/progenitor subtype expresses higher levels of lineage specifiers that regulate endodermal differentiation than the basal-like/squamous subtype.

FoxA1 and FoxA2 drive gastric differentiation and suppress squamous identity in NKX2-1-negative lung cancer.

Changes in cancer cell identity can alter malignant potential and therapeutic response. Loss of the pulmonary lineage specifier NKX2-1 augments the growth of KRAS-driven lung adenocarcinoma and causes pulmonary to gastric transdifferentiation. Here, we show that the transcription factors FoxA1 and FoxA2 are required for initiation of mucinous NKX2-1-negative lung adenocarcinomas in the mouse and for activation of their gastric differentiation program.