Canonical WNT signaling through Frizzled and LRP5/6 receptors is transduced to the WNT/β-
catenin and WNT/stabilization of proteins (STOP) signaling cascades to regulate cell fate and proliferation, whereas non-canonical WNT signaling through Frizzled or ROR receptors is transduced to the WNT/planar cell polarity (PCP), WNT/G protein-coupled receptor (GPCR) and WNT/
receptor tyrosine kinase (RTK) signaling cascades to regulate cytoskeletal dynamics and directional cell movement. WNT/β-
catenin signaling cascade crosstalks with RTK/SRK and GPCR-cAMP-PKA signaling cascades to regulate β-
catenin phosphorylation and β-
catenin-dependent transcription. Germline mutations in WNT signaling molecules cause hereditary
colorectal cancer,
bone diseases, exudative vitreoretinopathy,
intellectual disability syndrome and PCP-related diseases. APC or CTNNB1 mutations in colorectal, endometrial and
prostate cancers activate the WNT/β-
catenin signaling cascade. RNF43, ZNRF3, RSPO2 or RSPO3 alterations in breast, colorectal, gastric, pancreatic and other
cancers activate the WNT/β-
catenin, WNT/STOP and other WNT signaling cascades. ROR1 upregulation in
B-cell leukemia and solid
tumors and ROR2 upregulation in
melanoma induce invasion,
metastasis and therapeutic resistance through Rho-ROCK, Rac-JNK, PI3K-AKT and YAP signaling activation. WNT signaling in
cancer, stromal and immune cells dynamically orchestrate immune evasion and antitumor immunity in a cell context-dependent manner. Porcupine (PORCN), RSPO3, WNT2B, FZD5, FZD10, ROR1,
tankyrase and β-
catenin are targets of anti-WNT signaling
therapy, and
ETC-159,
LGK974, OMP-18R5 (vantictumab), OMP-54F28 (ipafricept), OMP-131R10 (rosmantuzumab),
PRI-724 and UC-961 (cirmtuzumab) are in clinical trials for
cancer patients. Different classes of anti-WNT signaling
therapeutics are necessary for the treatment of APC/CTNNB1-, RNF43/ZNRF3/RSPO2/RSPO3- and ROR1-types of human
cancers. By contrast, Dickkopf-related protein 1 (DKK1), SOST and
glycogen synthase kinase 3β (GSK3β) are targets of pro-WNT signaling
therapy, and anti-DKK1 (
BHQ880 and DKN-01) and anti-SOST (
blosozumab,
BPS804 and
romosozumab)
monoclonal antibodies are being tested in clinical trials for
cancer patients and osteoporotic post-menopausal women. WNT-targeting
therapeutics have also been applied as
reagents for in vitro stem-cell processing in the field of regenerative medicine.