Pleiotropic tumor suppressive functions of PTEN missense mutations during gliomagenesis.

PTEN plays a crucial role in preventing the development of glioblastoma (GBM), a severe and untreatable brain cancer. In GBM, most PTEN deficiencies are missense mutations that have not been thoroughly examined. Here, we leveraged genetically modified mice and isogenic astrocyte cell cultures to investigate the role of clinically relevant mutations (G36E, L42R, C105F, and R173H) in the development of EGFR-driven GBM.

Activation of WNT/β-Catenin Signaling Enhances Pancreatic Cancer Development and the Malignant Potential Via Up-regulation of Cyr61.

Pancreatic ductal adenocarcinoma (PDAC), a poor prognostic cancer, commonly develops following activating mutations in the KRAS oncogene. Activation of WNT signaling is also commonly observed in PDAC. To ascertain the impact of postnatal activation of WNT-stimulated signaling pathways in PDAC development, we combined the Elastase-tva-based RCAS-TVA pancreatic cancer model with the established LSL-Kras, Ptf1a-cre model.

KRAS(G12D)- and BRAF(V600E)-induced transformation of murine pancreatic epithelial cells requires MEK/ERK-stimulated IGF1R signaling.

Mutation of KRAS is a common initiating event in pancreatic ductal adenocarcinoma (PDAC). Yet, the specific roles of KRAS-stimulated signaling pathways in the transformation of pancreatic ductal epithelial cells (PDEC), putative cells of origin for PDAC, remain unclear. Here, we show that KRAS(G12D) and BRAF(V600E) enhance PDEC proliferation and increase survival after exposure to apoptotic stimuli in a manner dependent on MEK/ERK and PI3K/AKT signaling.

The activity of Gli transcription factors is essential for Kras-induced pancreatic tumorigenesis.

Pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive human malignancies, is thought to be initiated by KRAS activation. Here we find that transcriptional activation mediated by the Gli family of transcription factors, although dispensable for pancreatic development, is required for Kras-induced proliferation and survival in primary pancreatic epithelial cells in culture and for Kras-driven pancreatic intraepithelial neoplasia and PDAC formation in vivo. Further, ectopic Gli1 activation in the mouse pancreas accelerates Kras-driven tumor formation, underscoring the importance of Gli transcription factors in pancreatic tumorigenesis.