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Porcupine Inhibition Disrupts Mitochondrial Function and Homeostasis in WNT Ligand–Addicted Pancreatic Cancer

Overview of attention for article published in Molecular Cancer Therapeutics, March 2022
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About this Attention Score

  • Good Attention Score compared to outputs of the same age (69th percentile)
  • Good Attention Score compared to outputs of the same age and source (78th percentile)

Mentioned by

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9 tweeters

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1 Mendeley
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Title
Porcupine Inhibition Disrupts Mitochondrial Function and Homeostasis in WNT Ligand–Addicted Pancreatic Cancer
Published in
Molecular Cancer Therapeutics, March 2022
DOI 10.1158/1535-7163.mct-21-0623
Pubmed ID
Authors

Kristina Y. Aguilera, Thuc Le, Rana Riahi, Anna R. Lay, Stefan Hinz, Edris A. Saadat, Ajay A. Vashisht, James Wohlschlegel, Timothy R. Donahue, Caius G. Radu, David W. Dawson

Abstract

WNT signaling promotes pancreatic ductal adenocarcinoma (PDAC) through diverse effects on proliferation, differentiation, survival, and stemness. A subset of PDAC with inactivating mutations in ring finger protein 43 (RNF43) show growth dependency on autocrine WNT ligand signaling and are susceptible to agents that block WNT ligand acylation by Porcupine O-acyltransferase, which is required for proper WNT ligand processing and secretion. For this study, global transcriptomic, proteomic, and metabolomic analyses were performed to explore the therapeutic response of RNF43-mutant PDAC to the Porcupine inhibitor (PORCNi) LGK974. LGK974 disrupted cellular bioenergetics and mitochondrial function through actions that included rapid mitochondrial depolarization, reduced mitochondrial content, and inhibition of oxidative phosphorylation and tricarboxylic acid cycle. LGK974 also broadly altered transcriptional activity, downregulating genes involved in cell cycle, nucleotide metabolism, and ribosomal biogenesis and upregulating genes involved in epithelial-mesenchymal transition, hypoxia, endocytosis, and lysosomes. Autophagy and lysosomal activity were augmented in response to LGK974, which synergistically inhibited tumor cell viability in combination with chloroquine. Autocrine WNT ligand signaling dictates metabolic dependencies in RNF43-mutant PDAC through a combination of transcription dependent and independent effects linked to mitochondrial health and function. Metabolic adaptations to mitochondrial damage and bioenergetic stress represent potential targetable liabilities in combination with PORCNi for the treatment of WNT ligand-addicted PDAC.

Twitter Demographics

The data shown below were collected from the profiles of 9 tweeters who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 1 Mendeley reader of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 1 100%

Demographic breakdown

Readers by professional status Count As %
Unspecified 1 100%
Readers by discipline Count As %
Unspecified 1 100%

Attention Score in Context

This research output has an Altmetric Attention Score of 5. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 19 July 2022.
All research outputs
#5,732,745
of 21,606,563 outputs
Outputs from Molecular Cancer Therapeutics
#1,284
of 3,765 outputs
Outputs of similar age
#103,177
of 339,953 outputs
Outputs of similar age from Molecular Cancer Therapeutics
#9
of 41 outputs
Altmetric has tracked 21,606,563 research outputs across all sources so far. This one has received more attention than most of these and is in the 73rd percentile.
So far Altmetric has tracked 3,765 research outputs from this source. They typically receive more attention than average, with a mean Attention Score of 7.8. This one has gotten more attention than average, scoring higher than 65% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 339,953 tracked outputs that were published within six weeks on either side of this one in any source. This one has gotten more attention than average, scoring higher than 69% of its contemporaries.
We're also able to compare this research output to 41 others from the same source and published within six weeks on either side of this one. This one has done well, scoring higher than 78% of its contemporaries.