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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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Research Article Cell biology Oncology

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

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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 2

Time-series clustering reveals distinct dynamics of Wnt-regulated genes and enrichment for cell cycle and ribosome biogenesis.

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Time-series clustering reveals distinct dynamics of Wnt-regulated genes ...
(A) Time-series clustering of Wnt-activated genes reveals distinct patterns of response to PORCN inhibition. Genes differentially expressed over time (FDR < 10%) in response to PORCN inhibition were clustered by expression pattern using GP Clust. The cluster number (C) and TI50 for each cluster are indicated. (B) GO Biological Process enrichments of each cluster of Wnt-activated genes (hypergeometric test). Enrichment of Wnt-activated genes highlights processes, including Wnt signaling, ribosome biogenesis, and the cell cycle. (C) Illustration of the various time courses of gene expression following PORCN inhibition. Representative Wnt-activated genes from selected clusters are shown. TPM, transcripts per million reads. (D) Well-established Wnt/β-catenin target genes change with distinct dynamics following PORCN inhibition.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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