Temporal dynamics of Wnt-dependent transcriptome reveal an oncogenic Wnt/MYC/ribosome axis
Babita Madan, Nathan Harmston, Gahyathiri Nallan, Alex Montoya, Peter Faull, Enrico Petretto, David M. Virshup
Babita Madan, Nathan Harmston, Gahyathiri Nallan, Alex Montoya, Peter Faull, Enrico Petretto, David M. Virshup
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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

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Figure 1

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

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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%).