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Open research questions in Wnt/β-catenin signaling in development and cancer

106 gap statements mined from Wnt/β-catenin signaling in development and cancer papers in our 4.5M-paper local library, which holds 428 papers on the topic — drawn mostly from each paper's own stated research gap, future-work, challenge and limitation notes, and its abstract. The ones listed below are a selection still marked open; each names the study that raised it, with a DOI link where the paper has one.

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What the literature leaves open

  • Future research should focus on HNC-specific effector circuit characterization, direct MTDH inhibitor development, and prospective clinical validation.

    Metadherin: A pivotal oncogene and therapeutic target in head and neck cancer - a systematic review · 2026 · DOI

  • While MTDH-mediated EMT and chemoresistance have been extensively documented across multiple cancer types, including cervical cancer [19] and colorectal cancer [18,61], acidic extracellular pH has not been reported as a microenvironmental trigger for MTDH upregu- lation in any of these cancer types. This finding currently rests on a single NPC cell line (5–8 F), and prospective validation in broader HNC models is warranted to establish whether acidic pHe represents an HNC-specific microenvironmental inducer of MTDH.

    Metadherin: A pivotal oncogene and therapeutic target in head and neck cancer - a systematic review · 2026 · DOI

  • While our study confirms PDRG1 overexpression in human HCC, its specific biological functions and mechanisms in this suppressed significantly context remain incompletely defined.

    PDRG1 induced by SP1 facilitates the proliferation and metastasis of hepatocellular carcinoma by activating the Wnt/β-catenin pathway · 2026 · DOI

  • A key limitation remains small-molecule force field generation, which is a known broader issue in the computational chemistry community rather than a limitation unique to BFEE2.

    Computational Binding Affinities of Disheveled PDZ Protein-Ligand Complexes · 2026 · DOI

  • Furthermore, the HOXC9/NRP1 axis also remains to be explored in vivo. Knocking down HOXC9 holds great potential to promote the treatment response to anti-PD-L1 therapy and enhance anti-tumor immunity mediated by CD8 + T cells, represent- ing a promising strategy whose possibility remains to be validated by clinical investigations.

    HOXC9 transcriptionally activates NRP1 to promote cell malignant progression and immune evasion in colorectal cancer · 2026 · DOI

  • First, all functional characterization was performed in vitro; the in vivo efficacy, pharmacokinetics, and safety of the antibody remain to be estab- lished. This reciprocal regulation represents a major limitation of single-target strategies and may explain the partial rescue observed in our assays. Further preclinical and clinical evaluation is warranted to determine its therapeutic potential.

    A dual-action humanized DKK-1 antibody that activates the Wnt/β-catenin signaling pathway and inhibits the RANKL signaling pathway for osteoporosis therapy · 2026 · DOI

  • Additionally, it remains unclear whether nectin-4 knockdown enhances TMZ increased apoptosis, efficacy improved immune infiltration, or a combination of these processes. Future investigations examining AKT phosphorylation status following resveratrol treatment, as well as the use of specific pathway inhibitors, are warranted to definitively establish this regulatory axis.

    Targeting Nectin-4 sensitizes glioblastoma to temozolomide · 2026 · DOI

  • The reduced prevalence of these mutations following treatment warrants further investigation into whether CTNNB1 and RNF43 alterations confer treatment resistance or are preferentially eliminated by therapy.

    Precision Oncology Insights into WNT Pathway Alterations in FOLFOX-Treated Early-Onset Colorectal Cancer in High-Risk Populations · 2025 · DOI

  • It is nevertheless important to remember that this consensus is accepted for epithelial tumors and, although E- to N-cadherin switch is frequently used as a marker of EMT in cancers of other origins, the factual involvement of these proteins in processes akin to the EMT in non-epithelial tumors remains to be adequately studied and clarified. In fact, the mechanis- tic reciprocities between the expression of distinct cadherins have been already suggested, although poorly explored in tumor pathogenesis.

    Cadherin Expression Profiles Define Glioblastoma Differentiation and Patient Prognosis · 2024 · DOI

  • However, given the complexity of FEVR and the frequent need for treatment, we believe that these definitions are insufficient.

    Progression in familial exudative vitreoretinopathy: Long-term clinical course and baseline predictors · 2026 · DOI

  • Mat therefore warrants further investigation in thymoma-related models rather than being considered an established therapeutic strategy.

    Matrine suppresses thymoma stemness and apoptosis via YTH N6-methyladenosine RNA binding protein 1 and Wnt/β-catenin signaling · 2026 · DOI

  • There is limited data to inform decision between endoscopic surveillance and prophylactic total gastrectomy (PTG) in patients with early SRCC, which could have indolent behaviour.

    Predictors of early cancer burden in CDH1 pathogenic variant carriers: a UK single-centre cohort study · 2026 · DOI

  • Wnt signaling is a central driver of fibrotic progression across multiple tissues and organs; however, effective therapeutic strategies directly targeting Wnt signaling in fibrosis remain scarce.

    Wnt Signaling Pathway: Biological Function, Diseases, and Therapeutic Interventions · 2026 · DOI

  • However, the precise pathophysiological mechanisms underlying the disorder remain incompletely understood.

    An Adnp frameshift variant disrupts Wnt signalling inducing chromatocytoskeletal defects and autism-related behaviour in male mice · 2026 · DOI

  • BACKGROUND: Mitochondrial ribosomal protein L13 (MRPL13) has been implicated in tumor progression, but its relevance to esophageal squamous cell carcinoma (ESCC) remains insufficiently defined.

    MRPL13 sustains mitochondrial integrity and MAPK-associated aggressiveness in esophageal squamous cell carcinoma · 2026 · DOI

  • Mutations in a specific protein called calcium-activated nucleotidase 1 (Cant1) cause skeletal deformities, but the role of Cant1 in these deformities remains unclear.

    Dysregulation of the Cant1/β-Catenin/TCF4–CHSY1 Axis Underpins Impaired ECM Biosynthesis in Skeletal Disorders · 2026 · DOI

  • While recent studies have highlighted its pivotal roles in cancer cell proliferation and metastasis, a deeper mechanistic understanding of IQGAP3 is currently lacking.

    Wnt target IQGAP3 promotes Wnt signaling via disrupting Axin1-CK1α interaction · 2025 · DOI

  • We recently demonstrated that Celsr2 is essential for injury-induced responses and functions of astrocytes, while its role in the development and treatment of gliomas remains unexplored.

    Atypical cadherin CELSR2 acts as a therapeutic target for glioma through WNT3A/β-catenin signaling · 2025 · DOI

  • However, the exact function and underlying mechanisms of PLOD3 in CRC remains incompletely understood.

    Hypomethylation induced overexpression of PLOD3 facilitates colorectal cancer progression through TM9SF4-mediated autophagy · 2025 · DOI

  • Emerging evidence indicates that IRX3 plays critical roles in the development of some cancers, but the specific functions and molecular mechanisms of IRX3 in glioblastoma (GBM) remain unknown.

    IRX3-CDK14 axis promotes glioblastoma progression by regulating LRP6-mediated canonical Wnt/β-catenin pathway · 2025 · DOI

  • However, the mechanisms that control the stability of LZTS2 are not fully understood.

    SPOP and HAUSP bidirectionally regulate LZTS2 ubiquitination to modulate the Wnt pathway · 2025 · DOI

  • For this reason, further studies on this subject will be required in the coming years.

    Harnessing GSK-3β inhibition for lung cancer therapy: emerging opportunities and challenges · 2025 · DOI

  • We previously developed KY19382 and KY19334, small molecules that inhibit the cytosolic function of CXXC-type zinc finger protein 5 (CXXC5), as safe therapeutic agents to restore the suppressed Wnt/β-catenin signaling in several intractable diseases, but the effects of these small molecules on cancer have not been determined.

    Novel small molecules downregulate CDK1 expression and inhibit Wnt/β-catenin signaling in cutaneous squamous cell carcinoma by targeting its distinct tumor-specific cellular landscape · 2025 · DOI

  • However, the effectiveness of pharmacological therapy is limited by the emergence of resistance.

    Wnt Signaling in Hepatocellular Carcinoma: Biological Mechanisms and Therapeutic Opportunities · 2024 · DOI

  • Perineural invasion (PNI) leads to the poor prognosis of head and neck squamous cancer (HNSCC) patients, but the mechanism of PNI remains unclear.

    Dickkopf‐1 drives perineural invasion via PI3K–AKT signaling pathway in head and neck squamous cancer · 2024 · DOI

Most-cited papers in Wnt/β-catenin signaling in development and cancer

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106 gap statements have been mined from Wnt/β-catenin signaling in development and cancer papers in our 4.5M-paper local library, which holds 428 papers on the topic; the gaps come from whichever of those papers state one. They are mostly the research gaps the authors state and the papers' abstracts, plus future-work, limitations and challenges passages. The ones listed below are a selection still marked open; each names the study that raised it, with a DOI link where the paper has one, so you can read the original claim in context.

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