Editorial: Targeting the Wnt/β-catenin signaling pathway in cancer, volume II

Résumé fourni par la source

Canonical Wnt/β-catenin signaling lies at the crossroads of embryonic development, tissue homeostasis, and cancer. Under physiological conditions, this pathway regulates essential processes such as proliferation, cell fate, migration, survival, and stem cell renewal. In cancer, constitutive activation of Wnt/β-catenin signaling, for example, from mutations or aberrant overexpression of pathway components, can promote malignant transformation and sustain tumor growth, stem-like features, and interactions with the surrounding microenvironment. Wnt/β-catenin signaling can also influence tumor-immune interactions, as demonstrated by its association with dendritic cell dysfunction and T-cell exclusion in cancers.This dual role in maintaining cellular homeostasis, while being aberrantly activated in cancer has long complicated the therapeutic targeting of Wnt/β-catenin signaling. The challenge is not simply to inhibit the pathway, but how to selectively interfere with its oncogenic functions while preserving its essential roles in normal tissues to mitigate ontarget toxicities.The six contributions included in this Research Topic illustrate this complexity from different perspectives. Together, they show that Wnt/β-catenin activity can be shaped by non-coding RNAs, epitranscriptomic regulation, transcription factors, signals from the tumor microenvironment, cancer stem-cell states, and direct regulation of β-catenin itself.Rather than pointing to a single therapeutic solution, these studies suggest that the most effective strategy may depend on how, where, and at what stage of disease the pathway becomes dysregulated.Two studies explore upstream regulatory mechanisms in lung adenocarcinoma (LUAD). LGR5 also functions as a receptor for Rspondins, thereby enhancing Wnt/β-catenin signaling. Their analysis identifies LGR5positive cancer stem cells, inflammation, and the tumor microenvironment as emerging areas of interest, highlighting the growing attention to the interplay between Wnt signaling, cancer stemness, and the surrounding tumor niche.Finally, Trapani et al. focus on the therapeutic challenge of directly targeting β-catenin. βcatenin remains a difficult pharmacological target because it lacks conventional drugbinding pockets and also plays an essential structural role in cadherin-mediated cell adhesion. The authors discuss emerging strategies, including proteolysis-targeting chimeras (PROTACs), molecular glues, ubiquibodies, and other precision degraders. Of particular interest is the possibility of selectively degrading the oncogenic cytoplasmic and nuclear pools of β-catenin while preserving the membrane-associated pool required for adherens junctions. This approach may help overcome one of the major limitations of βcatenin-directed therapies by improving tumor selectivity while reducing on-target toxicity.Taken together, the articles in this Research Topic reinforce the idea that Wnt/β-catenin signaling should not be viewed as an isolated linear pathway. Its activity is shaped by multiple regulatory mechanisms and by the cellular and microenvironmental context in which tumor cells reside. Understanding these different levels of regulation will be essential for developing more selective and effective therapeutic strategies.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.