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.
Babita Madan, Nathan Harmston, Gahyathiri Nallan, Alex Montoya, Peter Faull, Enrico Petretto, David M. Virshup
Guidelines: The Editorial Board will only consider letters that we deem relevant and of interest to our readers. We will not post data that have not been subjected to peer review, nor will we post letters that are essentially a reiteration of another letter. We reserve the right to edit any letter for length, content, and clarity. Authors will be notified by e-mail if their letters were accepted. No appeals will be considered.
Specific requirements: All letters must be 400 words or fewer. You may enter the letter as plain text or HTML. The author's name and e-mail address are required, and will be posted with the letter. All possible conflicts of interest must be noted, even if they are not posted. If you wish to include a figure (keep in mind that non-peer-reviewed data will not be posted), please contact the editors directly at editors@the-jci.org.