WNT signaling and cancer stemness

Abstract

Cancer stemness, defined as the self-renewal and tumor-initiation potential of cancer stem cells (CSCs), is a cancer biology property featuring activation of CSC signaling networks. Canonical WNT signaling through Frizzled and LRP5/6 receptors is transmitted to the β-catenin-TCF/LEF-dependent transcription machinery to up-regulate MYC, CCND1, LGR5, SNAI1, IFNG, CCL28, CD274 (PD-L1) and other target genes. Canonical WNT signaling causes expansion of rapidly cycling CSCs and modulates both immune surveillance and immune tolerance. In contrast, noncanonical WNT signaling through Frizzled or the ROR1/2 receptors is transmitted to phospholipase C, Rac1 and RhoA to control transcriptional outputs mediated by NFAT, AP-1 and YAP-TEAD, respectively. Noncanonical WNT signaling supports maintenance of slowly cycling, quiescent or dormant CSCs and promotes epithelial–mesenchymal transition via crosstalk with TGFβ (transforming growth factor-β) signaling cascades, while the TGFβ signaling network induces immune evasion. The WNT signaling network orchestrates the functions of cancer-associated fibroblasts, endothelial cells and immune cells in the tumor microenvironment and fine-tunes stemness in human cancers, such as breast, colorectal, gastric and lung cancers. Here, WNT-related cancer stemness features, including proliferation/dormancy plasticity, epithelial–mesenchymal plasticity and immune-landscape plasticity, will be discussed. Porcupine inhibitors, β-catenin protein–protein interaction inhibitors, β-catenin proteolysis targeting chimeras, ROR1 inhibitors and ROR1-targeted biologics are investigational drugs targeting WNT signaling cascades. Mechanisms of cancer plasticity regulated by the WNT signaling network are promising targets for therapeutic intervention; however, further understanding of context-dependent reprogramming trajectories might be necessary to optimize the clinical benefits of WNT-targeted monotherapy and applied combination therapy for patients with cancer.

Glucocorticoid Receptor and β-Catenin Interact in Prostate Cancer Cells and Their Co-Inhibition Attenuates Tumorsphere Formation, Stemness, and Docetaxel Resistance

“…β-catenin participates in Wnt signaling during PCa progression and development of therapy resistance [ 35 ], and its expression in prostatic tissues mirrors GR expression [ 14 , 22 , 34 , 42 , 43 , 44 , 45 ]. Notably, β-catenin transcriptionally activates stemness and chemoresistance-associated genes, including CD44 , NANOG , MYC , and CXCR4 [ 46 , 47 , 48 , 49 , 50 ]. A recent study indicated that inhibition of the Wnt/β-catenin pathway in the presence of DTX in PCa cells downregulated genes linked to chemoresistance [ 38 ].…”

YTHDC1 Promotes Stemness Maintenance and Malignant Progression in Head and Neck Squamous Cell Carcinoma

“…In recent years, with continuous research in the field of molecular biology, CSCs have been found to play an important role in tumor development, invasion, metastasis, chemoresistance, and radioresistance [22][23][24]. The repopulation and differentiation of CSCs often lead to disease recurrence and play an important role in poor prognosis.…”

The role of Evi/Wntless in exporting Wnt proteins

“…More frequently, aberrant Wnt secretion is associated with cancer progression or tumour immune response in various tissues ( Table 1 ) (reviewed by Galluzzi et al, 2019 , and Katoh and Katoh, 2022 ). Mutations in Wnt pathway components are especially abundant in colorectal cancer, affecting nearly all clinical cases ( Cancer Genome Atlas Network, 2012 ; Yaeger et al, 2018 ; Zehir et al, 2017 ; Zhan et al, 2017 ).…”