Temporal dynamics of Wnt-dependent transcriptome reveal an oncogenic Wnt/MYC/ribosome axis
Babita Madan, … , Enrico Petretto, David M. Virshup
Babita Madan, … , Enrico Petretto, David M. Virshup
Published April 30, 2019; First published October 9, 2018
Citation Information: J Clin Invest. 2018;128(12):5620-5633. https://doi.org/10.1172/JCI122383.
View: Text | PDF
Research Article Cell biology Oncology

Temporal dynamics of Wnt-dependent transcriptome reveal an oncogenic Wnt/MYC/ribosome axis

Abstract

Activating mutations in the Wnt pathway drive a variety of cancers, but the specific targets and pathways activated by Wnt ligands are not fully understood. To bridge this knowledge gap, we performed a comprehensive time-course analysis of Wnt-dependent signaling pathways in an orthotopic model of Wnt-addicted pancreatic cancer, using a porcupine (PORCN) inhibitor currently in clinical trials, and validated key results in additional Wnt-addicted models. The temporal analysis of the drug-perturbed transcriptome demonstrated direct and indirect regulation of more than 3,500 Wnt-activated genes (23% of the transcriptome). Regulation was both via Wnt/β-catenin and through the modulation of protein abundance of important transcription factors, including MYC, via Wnt-dependent stabilization of proteins (Wnt/STOP). Our study identifies a central role of Wnt/β-catenin and Wnt/STOP signaling in controlling ribosome biogenesis, a key driver of cancer proliferation.

Authors

Babita Madan, Nathan Harmston, Gahyathiri Nallan, Alex Montoya, Peter Faull, Enrico Petretto, David M. Virshup

×

Figure 1

PORCN inhibition remodels the morphology and transcriptome of RNF43 mutant pancreatic cancer.

Options: View larger image (or click on image) Download as PowerPoint
PORCN inhibition remodels the morphology and transcriptome of RNF43 muta...
(A) ETC-159 treatment prevents the growth of orthotopic HPAF-II xenografts. HPAF-II cells (106) were injected into the tail of the mouse pancreas. Following establishment of tumors (~3 weeks), the mice were treated daily with 30 mg/kg ETC-159. Tumor growth was monitored by measuring luciferase activity. Data represent mean ± SD. n = 8/group. (B) Inhibition of Wnt signaling promotes histological changes in HPAF-II xenografts. H&E-stained images of HPAF-II xenografts treated with ETC-159 for 28 days. (C) Schematic representation of the experimental plan. HPAF-II cells (106) were injected into the tail of the mouse pancreas. Following establishment of tumors (28 days), the mice were treated twice daily with 37.5 mg/kg doses of ETC-159. Tumors were harvested at the indicated time points. (D) ETC-159 treatment leads to widespread changes in the transcriptome. Total number of genes whose expression changes after PORCN inhibition over time compared with at 0 hours. Genes whose expression was up- or downregulated at the previous time point are also indicated (absolute fold change > 1.5, FDR < 10%).