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Cells
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From Mechanisms to Therapeutics: Wnt Signaling in Cancer—Second Edition
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From Mechanisms to Therapeutics: Wnt Signaling in Cancer—Second Edition

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: 20 March 2025 | Viewed by 4608

Special Issue Editors

Dr. Anitha K. Shenoy

E-Mail Website
Guest Editor
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, California Health Sciences University, Clovis, California, USA
Interests: Wnt signaling; signal transduction; cancer biology; stem cells; cancer stem cells; angiogenesis
Special Issues, Collections and Topics in MDPI journals
Dr. Liya Pi

E-Mail Website
Guest Editor
Department of Pathology and Laboratory Medicine, Tulane University, New Orleans, LA 70112, USA
Interests: hepatic progenitor cell activation; liver regeneration; alcoholic fibrosis; liver cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The Wnt signaling pathway plays a central role in human development, tissue homeostasis, and a plethora of diseases including cancer.  It is well-recognized that the canonical as well as non-canonical Wnt signaling pathways are closely associated with tumor initiation, progression, and metastasis. The canonical Wnt signaling also regulates the formation and maintenance of embryonic, adult, and cancer stem cells. In addition, there exists a complex relationship between Wnt signaling and the tumor microenvironment that promotes cancer cell proliferation.  As a result, the Wnt signaling pathway and its components have become attractive drug targets for cancer treatment.

However, cancer drug development efforts aimed at Wnt signaling have been largely unsuccessful due to the ubiquitous nature of this pathway in health and disease. A thorough understanding of the Wnt mechanism in cancer pathophysiology, its role in conferring drug resistance, and the impact of its inhibition on cancer treatment are warranted to develop effective therapeutic strategies. In this regard, we welcome original articles and reviews for this Special Issue. Topics of interest include, but are not limited to, the following:

  1. Wnt signaling in tumorigenesis and development of cancer;
  2. Targeting Wnt signaling in cancer;
  3. Wnt signaling and drug resistance in cancer;
  4. Wnt signaling and the tumor microenvironment;
  5. Wnt signaling and cancer stem cells;
  6. Strategies to employ Wnt signaling pathway modulators in cancer treatment.

Dr. Anitha K. Shenoy
Dr. Liya Pi
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Wnt
  • β-catenin
  • development
  • homeostasis
  • cancer
  • cancer stem cells (CSC)
  • targeted cancer therapy
  • canonical Wnt signaling
  • non-canonical Wnt signaling

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Related Special Issue

Published Papers (4 papers)

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Research

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16 pages, 6979 KiB  
Article
A Necessary Role for Cyclin D2 Induction During Colon Cancer Progression Mediated by L1
by Arka Saha, Nancy Gavert, Thomas Brabletz and Avri Ben-Ze’ev
Cells 2024, 13(21), 1810; https://doi.org/10.3390/cells13211810 - 2 Nov 2024
Viewed by 710
Abstract
The cell adhesion molecule L1CAM (L1), mainly known for its function in brain cells, is a Wnt/β-catenin signaling target gene in colorectal cancer (CRC) cells, where it promotes invasion and liver metastasis. We interrogated which genes are expressed at increased levels in human [...] Read more.
The cell adhesion molecule L1CAM (L1), mainly known for its function in brain cells, is a Wnt/β-catenin signaling target gene in colorectal cancer (CRC) cells, where it promotes invasion and liver metastasis. We interrogated which genes are expressed at increased levels in human CRC tissue and induced in CRC cell lines overexpressing L1. We found increased cyclin D2 levels in CRC tissue and LS 174T and HCT 116 human CRC cells overexpressing L1. Increased cyclin D2 in CRC cells was associated with higher proliferation rates, faster motility, tumorigenesis, and liver metastasis. The suppression of cyclin D2 expression by shRNA to cyclin D2 blocked the increase in these cellular properties of L1-expressing cells. The overexpression of cyclin D2 in the absence of L1 also conferred tumorigenic properties similar to L1 expression. The pathways involved in the elevation of cyclin D2 by L1 include NF-κB, Akt, and β-catenin signaling but not the Erk pathway. We found that in a significant percentage of human CRC tissue samples, cyclin D2 is expressed at high levels in the nuclei of cancer cells. At the same time, the adjacent normal mucosa was negative for cyclin D2 staining. The results suggest that the increased cyclin D2 expression by L1 is required to induce proliferative, motile tumor development in CRC tissue and can serve as a diagnostic marker and a target for CRC therapy. Full article
(This article belongs to the Special Issue From Mechanisms to Therapeutics: Wnt Signaling in Cancer—Second Edition)
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13 pages, 16328 KiB  
Article
Exploring DIX-DIX Homo- and Hetero-Oligomers in Wnt Signaling with AlphaFold2
by Zehua Wen, Lei Wang, Shi-Wei Liu, Hua-Jun Shawn Fan, Jong-Won Song and Ho-Jin Lee
Cells 2024, 13(19), 1646; https://doi.org/10.3390/cells13191646 - 3 Oct 2024
Viewed by 827
Abstract
Wnt signaling is involved in embryo development and cancer. The binding between the DIX domains of Axin1/2, Dishevelled1/2/3, and Coiled-coil-DIX1 is essential for Wnt/β-catenin signaling. Structural and biological studies have revealed that DIX domains are polymerized through head-to-tail interface interactions, which are indispensable [...] Read more.
Wnt signaling is involved in embryo development and cancer. The binding between the DIX domains of Axin1/2, Dishevelled1/2/3, and Coiled-coil-DIX1 is essential for Wnt/β-catenin signaling. Structural and biological studies have revealed that DIX domains are polymerized through head-to-tail interface interactions, which are indispensable for activating β-catenin Wnt signaling. Although different isoforms of Dvl and Axin proteins display both redundant and specific functions in Wnt signaling, the specificity of DIX-mediated interactions remains unclear due to technical challenges. Using AlphaFold2(AF2), we predict the structures of 6 homodimers and 22 heterodimers of DIX domains without templates and compare them with the reported X-ray complex structures. PRODIGY is used to calculate the binding affinities of these DIX complexes. Our results show that the Axin2 DIX homodimer has a stronger binding affinity than the Axin1 DIX homodimer. Among Dishevelled (Dvl) proteins, the binding affinity of the Dvl1 DIX homodimer is stronger than that of Dvl2 and Dvl3. The Coiled-coil-DIX1(Ccd1) DIX homodimer shows weaker binding than the Axin1 DIX homodimer. Generally, heterodimer interactions tend to be stronger than those of homodimers. Our findings provide insights into the mechanism of the Wnt signaling pathway and highlight the potential of AF2 and PRODIGY for studying protein–protein interactions in signaling pathways. Full article
(This article belongs to the Special Issue From Mechanisms to Therapeutics: Wnt Signaling in Cancer—Second Edition)
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17 pages, 1910 KiB  
Article
Synthetic Lethality between Cohesin and WNT Signaling Pathways in Diverse Cancer Contexts
by Maria Michela Pallotta, Maddalena Di Nardo and Antonio Musio
Cells 2024, 13(7), 608; https://doi.org/10.3390/cells13070608 - 30 Mar 2024
Viewed by 1931
Abstract
Cohesin is a highly conserved ring-shaped complex involved in topologically embracing chromatids, gene expression regulation, genome compartmentalization, and genome stability maintenance. Genomic analyses have detected mutations in the cohesin complex in a wide array of human tumors. These findings have led to increased [...] Read more.
Cohesin is a highly conserved ring-shaped complex involved in topologically embracing chromatids, gene expression regulation, genome compartmentalization, and genome stability maintenance. Genomic analyses have detected mutations in the cohesin complex in a wide array of human tumors. These findings have led to increased interest in cohesin as a potential target in cancer therapy. Synthetic lethality has been suggested as an approach to exploit genetic differences in cancer cells to influence their selective killing. In this study, we show that mutations in ESCO1, NIPBL, PDS5B, RAD21, SMC1A, SMC3, STAG2, and WAPL genes are synthetically lethal with stimulation of WNT signaling obtained following LY2090314 treatment, a GSK3 inhibitor, in several cancer cell lines. Moreover, treatment led to the stabilization of β-catenin and affected the expression of c-MYC, probably due to the occupancy decrease in cohesin at the c-MYC promoter. Finally, LY2090314 caused gene expression dysregulation mainly involving pathways related to transcription regulation, cell proliferation, and chromatin remodeling. For the first time, our work provides the underlying molecular basis for synthetic lethality due to cohesin mutations and suggests that targeting the WNT may be a promising therapeutic approach for tumors carrying mutated cohesin. Full article
(This article belongs to the Special Issue From Mechanisms to Therapeutics: Wnt Signaling in Cancer—Second Edition)
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Review

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22 pages, 2206 KiB  
Review
Structural and Functional Insights into Dishevelled-Mediated Wnt Signaling
by Lei Wang, Rui Zhu, Zehua Wen, Hua-Jun Shawn Fan, Teresa Norwood-Jackson, Danielle Jathan and Ho-Jin Lee
Cells 2024, 13(22), 1870; https://doi.org/10.3390/cells13221870 - 11 Nov 2024
Viewed by 558
Abstract
Dishevelled (DVL) proteins precisely control Wnt signaling pathways with many effectors. While substantial research has advanced our understanding of DVL’s role in Wnt pathways, key questions regarding its regulatory mechanisms and interactions remain unresolved. Herein, we present the recent advances and perspectives on [...] Read more.
Dishevelled (DVL) proteins precisely control Wnt signaling pathways with many effectors. While substantial research has advanced our understanding of DVL’s role in Wnt pathways, key questions regarding its regulatory mechanisms and interactions remain unresolved. Herein, we present the recent advances and perspectives on how DVL regulates signaling. The experimentally determined conserved domain structures of DVL in conjunction with AlphaFold-predicted structures are used to understand the DVL’s role in Wnt signaling regulation. We also summarize the role of DVL in various diseases and provide insights into further directions for research on the DVL-mediated signaling mechanisms. These findings underscore the importance of DVL as a pharmaceutical target or biological marker in diseases, offering exciting potential for future biomedical applications. Full article
(This article belongs to the Special Issue From Mechanisms to Therapeutics: Wnt Signaling in Cancer—Second Edition)
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