Back to the drawing board: Re-thinking the role of GLI1 in pancreatic carcinogenesis

Abstract

Aberrant activation of the transcription factor GLI1, a central effector of the Hedgehog (HH) pathway, is associated with several malignancies, including pancreatic ductal adenocarcinoma (PDAC), one of most deadly human cancers. GLI1 has been described as an oncogene in PDAC, making it a promising target for drug therapy. Surprisingly, clinical trials targeting HH/GLI1 axis in advanced PDAC were unsuccessful, leaving investigators questioning the mechanism behind these failures. Recent evidence suggests the loss of GLI1 in the later stages of PDAC may actually accelerate disease. This indicates GLI1 may play a dual role in PDAC, acting as an oncogene in the early stages of disease and a tumor-suppressor in the late stages.