Wnt signaling pathways in biology and disease: mechanisms and therapeutic advances

Abstract

The Wnt signaling pathway is critically involved in orchestrating cellular functions such as proliferation, migration, survival, and cell fate determination during development. Given its pivotal role in cellular communication, aberrant Wnt signaling has been extensively linked to the pathogenesis of various diseases. This review offers an in-depth analysis of the Wnt pathway, detailing its signal transduction mechanisms and principal components. Furthermore, the complex network of interactions between Wnt cascades and other key signaling pathways, such as Notch, Hedgehog, TGF-β, FGF, and NF-κB, is explored. Genetic mutations affecting the Wnt pathway play a pivotal role in disease progression, with particular emphasis on Wnt signaling's involvement in cancer stem cell biology and the tumor microenvironment. Additionally, this review underscores the diverse mechanisms through which Wnt signaling contributes to diseases such as cardiovascular conditions, neurodegenerative disorders, metabolic syndromes, autoimmune diseases, and cancer. Finally, a comprehensive overview of the therapeutic progress targeting Wnt signaling was given, and the latest progress in disease treatment targeting key components of the Wnt signaling pathway was summarized in detail, including Wnt ligands/receptors, β-catenin destruction complexes, and β-catenin/TCF transcription complexes. The development of small molecule inhibitors, monoclonal antibodies, and combination therapy strategies was emphasized, while the current potential therapeutic challenges were summarized. This aims to enhance the current understanding of this key pathway.

Fig. 1

Canonical Wnt pathway signaling. Canonical Wnt pathway signaling operates in two distinct states: activation and inactivation. In the inactive state, the pathway is primarily governed by the destruction complex. Activation of the pathway necessitates the binding of Wnt ligands to their receptors. LRP lipoprotein receptor-related protein, Dvl/Dsh disheveled, GSK3β glycogen synthase kinase 3β, CK1α casein kinase 1α, APC adenomatous polyposis coli, PP2A protein phosphatase 2 A, β-TrCP β-transduction repeat-containing E3 ubiquitin-protein ligase, TCF/LEF T cell factor/lymphoid enhancer factor, TNKS Tankyrases, CBP cyclic AMP response element-binding protein, VEGF vascular endothelial growth factor, EGFR epidermal growth factor receptor, SOX sex-determining region Y-box. Image created with BioRender (https://biorender.com/)

Fig. 2

Non-canonical Wnt pathway signaling encompasses two major branches: the Wnt/PCP (Planar Cell Polarity) pathway and the Wnt/Ca²⁺ pathway. Dvl/Dsh disheveled, DAAM1 Disheveled-associated activator of morphogenesis 1, JNK Jun N-terminal kinase, ROCK Rho-associated kinase, PLC phospholipase C, IP3 inositol triphosphate, Ca2+ calcium, cGMP 3’,5’-Cyclic guanosine monophosphate, NFAT nuclear factor of activated T cells, CaMKII Calcium-calmodulin (CaM)-dependent protein kinase II, TAK1 TGF-beta-activated kinase 1, NLK Nemo-like kinase, PKC protein kinase C, TCF/LEF T cell factor/lymphoid enhancer factor, CREB cAMP-response element binding protein. Image created with BioRender (https://biorender.com/)

Fig. 3

Overview diagram of Hedgehog pathway, Notch pathway and TGF-β pathway. Hh Hedgehog, SHH Sonic Hedgehog, IHH Indian Hedgehog, DHH Desert Hedgehog, PTC Patched, SMO Smoothened, Cos2 Costal 2, Fu fused, Ci/Gli Cubitus interruptus/Gli, JAG Jagged, DLL Delta-like, NICD Notch intracellular domain, NECD Notch extracellular domain, EGF epidermal growth factor, LNR LIN12-Notch repeat, TGF-β transforming growth factor-β, SARA Smad anchor for receptor activation. Image created with BioRender (https://biorender.com/)

Fig. 4

Crosstalk between Wnt and FGF signaling pathways. Dvl/Dsh disheveled, PLC phospholipase C, IP3 inositol triphosphate, Ca2+ calcium, DAG diacylglycerol, PKC protein kinase C, GSK3β glycogen synthase kinase 3β, PIP2 phosphatidylinositol bisphosphate, FRS2 fibroblast growth factor receptor substrate 2, JAK Janus kinase, STAT signal transducer and activator of transcription, GRB2 growth factor receptor-bound protein 2, GAB1 GRB2-associated binder 1, PI3K phosphatidylinositol 3-kinase, PDK phosphoinositide-dependent kinases, AKT protein kinase B, SOS son of sevenless, MAPK mitogen-activated protein kinases, ERK extracellular-signal-regulated kinases. Image created with BioRender (https://biorender.com/)

Fig. 5

Wnt signaling pathway in cancer stem cells (CSCs). a Common CSC marker. b Primary causes of CSCs’ high drug resistance. c Potential role of the Wnt signaling pathway in CSC across various tumors. ROR1/2 receptor tyrosine kinase-like orphan receptor 1 and 2, RYK tyrosine kinases, ZNF3 zinc fingers 3, RNF43 RING finger protein 43, LRP lipoprotein receptor-related protein, LGR5 leucine-rich repeat-containing G protein-coupled receptor 5, EGCG epigallocatechin-3-gallate, CSC cancer stem cell, RSPO R-spondin. Image created with BioRender (https://biorender.com/)

Fig. 6

The Wnt signaling pathway plays a crucial role in modulating the immune microenvironment of tumors. Wnt activation suppresses the secretion of CCL4 and reduces the infiltration and activation of dendritic cells in tumor cells. Regulatory destruction complexes play a vital role in maintaining immunological tolerance by aiding in the development of regulatory T cells and fostering T cell unresponsiveness or apoptosis. Furthermore, Wnt signaling plays a vital role in modulating the equilibrium among various macrophage phenotypes. DC dendritic cell, IDO1 Indoleamine 2,3-dioxygenase 1, TGF Transforming growth factor, CCL4 C-C motif chemokine ligand 4, IL Interleukin. Image created with BioRender (https://biorender.com/)

Fig. 7

Dysregulated Wnt signaling is linked to several human neurodegenerative diseases, including Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). In PD, Wnt signaling could active nuclear receptor-related 1 (Nurr1), a transcription factor critical for the development, differentiation, and maintenance of midbrain dopaminergic neurons. In AD, the deletion of the neuronal LRP6 gene results in the downregulation of Wnt signaling, leading to amyloid pathology. In HD, Wnt/β-catenin signaling is activated in human HD brain tissue. Additionally, Wnt5a has been shown to protect motor neurons through the non-canonical Wnt/Ca2⁺ signaling pathway in ALS. Image created with BioRender (https://biorender.com/)

Fig. 8

Overview of the Wnt signaling pathway in various cancers, including colorectal cancer, hepatocellular carcinoma, lung cancers, chronic myeloid leukemia, triple-negative breast cancer, melanoma, and glioblastoma multiforme. Hyperactivation of Wnt signal, as a driving factor of cancers, affects tumor proliferation, invasion, migration, EMT, Stemness-like properties and drug resistance. CK1α casein kinase 1α, APC adenomatous polyposis coli, GSK3β glycogen synthase kinase 3β, HNF4α hepatocyte nuclear factor α, GREB1 growth regulation by estrogen in breast cancer 1, RNF146 RING finger protein 146, UBC9 ubiquitin-conjugating enzyme 9, PIAS3 protein inhibitor of activated STAT3, DAAM1 disheveled-associated activator of morphogenesis 1, JNK c-Jun N-terminal kinase, DVL3 disheveled 3, ZFX zinc finger protein X-linked, BCR/ABL breakpoint cluster region-c-Abelson murine leukemia viral oncogene homolog, MITF microphthalmia-associated transcription factor, PGC1α peroxisome proliferator-activated receptor gamma coactivator 1α, PI3K phosphatidylinositol 3-kinase, mTOR mammalian target of rapamycin, EMT epithelial-mesenchymal transition, PCP planar cell polarity, LRP5 lipoprotein receptor-related protein 5, TCF/LEF T cell factor/lymphoid enhancer factor, TSPAN12 tetraspanin 12, ASCL1 achaete-scute family bHLH transcription factor 1, APC Adenomatous polyposis coli, CRC Colorectal cancer, HCC Hepatocellular carcinoma, SCLC Small cell lung cancer, NSCLC Non-small cell lung cancer, TNBC Triple-negative breast cancer, CML Chronic myeloid leukemia, GBM Glioblastoma multiforme. Image created with BioRender (https://biorender.com/)

Fig. 9

Small molecule therapeutic drug map targeting all parts of the Wnt pathway. On the left side of the picture are the tumor types that can be treated with small molecule drugs, and on the right side of the picture are the various categories of small molecule drugs. RSPO R-spondin, DKK Dickkopf, FZD Frizzled, ROR receptor tyrosine kinase-like orphan receptor, LRP lipoprotein receptor-related protein, Dvl/Dsh disheveled, GSK3β glycogen synthase kinase 3β, APC adenomatous polyposis coli, PP2A protein phosphatase 2A, CK1α casein kinase 1α, ROR1/2 receptor tyrosine kinase-like orphan receptor 1 and 2, RYK tyrosine kinases, PORCN Porcupine, COX cyclooxygenase, CBP cyclic AMP response element-binding protein, TCF/LEF T cell factor/lymphoid enhancer factor. Image created with BioRender (https://biorender.com/)