A new validated mathematical model of the Wnt signalling pathway predicts effective combinational therapy by sFRP and Dkk

The Biochemical Journal
Yuri KoganZvia Agur

Abstract

The Wnt signalling pathway controls cell proliferation and differentiation, and its deregulation is implicated in different diseases including cancer. Learning how to manipulate this pathway could substantially contribute to the development of therapies. We developed a mathematical model describing the initial sequence of events in the Wnt pathway, from ligand binding to β-catenin accumulation, and the effects of inhibitors, such as sFRPs (secreted Frizzled-related proteins) and Dkk (Dickkopf). Model parameters were retrieved from experimental data reported previously. The model was retrospectively validated by accurately predicting the effects of Wnt3a and sFRP1 on β-catenin levels in two independent published experiments (R(2) between 0.63 and 0.91). Prospective validation was obtained by testing the model's accuracy in predicting the effect of Dkk1 on Wnt-induced β-catenin accumulation (R(2)≈0.94). Model simulations under different combinations of sFRP1 and Dkk1 predicted a clear synergistic effect of these two inhibitors on β-catenin accumulation, which may point towards a new treatment avenue. Our model allows precise calculation of the effect of inhibitors applied alone or in combination, and provides a flexible framework...Continue Reading

References

Jun 24, 1997·Proceedings of the National Academy of Sciences of the United States of America·P W FinchJ S Rubin
Mar 31, 1999·Proceedings of the National Academy of Sciences of the United States of America·J C HsiehJ Nathans
Oct 9, 1999·The Journal of Biological Chemistry·B N KholodenkoJ B Hoek
Jul 13, 2001·Current Biology : CB·M V SemënovX He
Sep 3, 2002·The Journal of Biological Chemistry·Chi-hwa Wu, Roel Nusse
Jun 5, 2003·Biochimica Et Biophysica Acta·Rachel H GilesHans Clevers
Jan 21, 2004·Molecular Cell·Keiko TamaiXi He
Jan 11, 2005·The Journal of Pathology·Mohammad Ilyas
Nov 19, 2005·The Biochemical Journal·Richard J OrtonWalter Kolch
Jan 21, 2006·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Lisa M GalliLaura W Burrus
Jan 31, 2006·Journal of Cell Science·Ken M Cadigan, Yan I Liu
Apr 8, 2006·Annals of Oncology : Official Journal of the European Society for Medical Oncology·C MassardJ-C Soria
May 4, 2006·The Journal of Pharmacology and Experimental Therapeutics·Ronald J Tallarida
Nov 23, 2006·BMC Neuroscience·Edda Klipp, Wolfram Liebermeister
Dec 26, 2006·Cellular Signalling·Akira KikuchiShosei Kishida
Apr 28, 2007·Biochemical and Biophysical Research Communications·Danuta WawrzakLuc Leyns
Jan 15, 2008·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Hans A Kestler, Michael Kühl
Mar 7, 2008·Journal of Cell Science·Paola BovolentaJavier Lopez-Rios
Mar 15, 2008·Current Opinion in Cell Biology·He Huang, Xi He
Apr 25, 2008·Nature Reviews. Cancer·Alexandra Klaus, Walter Birchmeier
Jan 17, 2009·Cancer Research·Alejandra C VenturaSofia D Merajver
Mar 17, 2009·Journal of Mathematical Biology·Gary R MiramsJohn R King
Jul 22, 2009·Developmental Cell·Bryan T MacDonaldXi He
Jan 23, 2010·The Journal of Biological Chemistry·Eric BourhisRami N Hannoush
Jun 10, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Naoko Takebe, S Percy Ivy
Jun 10, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Fumi Takahashi-Yanaga, Michael Kahn
Sep 25, 2010·Biochemical Society Transactions·Bente Kofahl, Jana Wolf
Oct 14, 2010·Journal of Cell Science·Noriko YokoyamaCraig C Malbon

❮ Previous
Next ❯

Citations

Apr 5, 2013·Wiley Interdisciplinary Reviews. Systems Biology and Medicine·Bethan Lloyd-LewisHelen M Byrne
Jun 25, 2015·Carcinogenesis·Sabine A S LangieAndrew R Collins
Oct 7, 2014·Drug Discovery Today·Stacey D FinleyAleksander S Popel
Jul 20, 2016·PLoS Computational Biology·Diego A VargasMuhammad H Zaman
Oct 18, 2013·Scientific Reports·Ju BaoJie J Zheng
Dec 19, 2017·Frontiers in Physiology·Bruno ChristNavina Waschinsky
Oct 11, 2017·Theoretical Biology & Medical Modelling·Kelsey GasiorSudin Bhattacharya
Aug 6, 2021·PLoS Computational Biology·Kai BuddeAdelinde M Uhrmacher

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.

Related Papers

Physical Biology
Aidan MacNamaraJulio Saez-Rodriguez
Bioinformatics
Stefan HoopsUrsula Kummer
Journal of Cell Science
Yoshiaki Kawano, Robert Kypta
© 2022 Meta ULC. All rights reserved