日本分子生物学会/日本生化学会

16:45 〜 18:45

[2LBA038] Genetic Ablation of Smoothened in Tumor-Associated Fibroblasts Promotes Pancreatic Cancer Initiation

〇Xin Liu1,2、Jinghai Wu1,2、Jason R. Pitarresi1,2、Veronica Bravo1,2、Ostrowski Michael1,2 (1.Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA、2.Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, Ohio 43210, USA)

Pancreatic tumor, Pten, Smo inhibitor, Hedgehog pathway, TGFa

The contribution of the tumor microenvironment to pancreatic adenocarcinoma (PDAC) development is currently unclear. Here we show the genetic inactivation of Smoothened (Smo) in stromal fibroblasts accelerated Kras-initiated tumorigenesis. The mechanism involved destabilization of fibroblast PTEN protein. An unbiased genetic screen revealed the ubiquitin E2 conjugating enzyme UBE2K as a PTEN destabilizer and knockdown of UBE2K blocked the degradation of PTEN protein. Down-regulation of PTEN enhanced TGF-a production in stromal fibroblasts via transcription factor Gli2, and increased epithelial cell transformation and proliferation. A SMO inhibitor, GDC-0449, decreased PTEN in a Kras model and in human pancreatic tumor fibroblasts. Importantly, in PDAC patient samples, low PTEN expression correlated with low SMO expression and with reduced overall survival. The results define a pathway that reprograms stromal fibroblasts from tumor suppressive to tumor promoting. Thus, a more comprehensive understanding of tumor-stroma interactions is required to assure effective implementation of targeted therapies.