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 October 9, 2018
Citation Information: J Clin Invest. 2018;128(12):5620-5633. https://doi.org/10.1172/JCI122383.
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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 5

Stabilized MYC partially reverses the effects of Wnt inhibition.

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Stabilized MYC partially reverses the effects of Wnt inhibition. (A) Exp...
(A) Expression of nonendogenous Myc transcripts in MYC OE or MYC T58A tumors does not change with ETC-159 treatment, in contrast to the response of the endogenous MYC transcript in the HPAF-II tumors. Right: range of MYC expression in clinical pancreatic ductal adenocarcinomas (PDAC) and colon adenocarcinomas (COAD) sequenced as part of the TCGA. The Myc expression in MYC OE is comparable to the range observed in clinical samples. (B) MYC T58A cancers are partially responsive to Wnt inhibition. HPAF-II cells, MYC OE, or MYC T58A HPAF-II cells were injected into the pancreas as before. Following the establishment of tumors, mice were treated daily with 30 mg/kg ETC-159. Tumor weights after 28 days of treatment are shown. n = 5–9 mice/group. Overall differences were assessed using nonparametric 2-way ANOVA (condition, P = 0.0056; treatment, P < 2 × 10–16). Pairwise differences between conditions were assessed using post hoc Mann-Whitney U test (2 tailed). TGI, tumor growth inhibition. (C) Ectopically expressed MYC is sensitive to GSK3-mediated degradation. ETC-159 treatment reduces the protein abundance of both endogenous and ectopically expressed MYC in HPAF-II and MYC OE tumors. Mutation of the GSK3 phosphorylation site prevents the decrease in MYC protein abundance in response to Wnt inhibition in the HPAF-II (T58A) tumors. Ratios of MYC levels to β-actin levels for each lane are indicated.