FAT1, also known as FAT atypical cadherin 1, encodes a protocadherin. It serves as a molecular "brake" on mitochondrial respiration, acts as a receptor for signaling pathways regulating cell-cell contact interaction and planar cell polarity, and activates pathways like Wnt/β-catenin, Hippo, and MAPK/ERK, affecting cell proliferation, migration, and invasion [2,4]. Its abnormal expression is linked to tumor development. Genetic models, such as KO/CKO mouse models, are valuable for studying its function.

In mouse models of skin squamous cell carcinoma and lung tumors, deletion of Fat1 accelerates tumor initiation and malignant progression, promotes a hybrid epithelial-to-mesenchymal transition (EMT) phenotype, increases tumor stemness, and spontaneous metastasis [1]. The loss-of-function of FAT1 activates a CAMK2-CD44-SRC axis promoting YAP1 nuclear translocation and ZEB1 expression for the mesenchymal state, and inactivates EZH2 to promote SOX2 expression for the epithelial state [1]. In breast cancer, FAT1 loss leads to marked elevations in CDK6, causing resistance to CDK4/6 inhibitors via the Hippo pathway [3]. In head and neck squamous cell cancer, FAT1 mutations are associated with resistance to immunotherapy [5].

In conclusion, Fat1 plays a crucial role in maintaining normal biological functions, especially in processes related to cell-cell interactions and signaling pathways. Model-based research, particularly Fat1 KO/CKO mouse models, has revealed its significance in cancer-related disease areas, such as squamous cell carcinomas, breast cancer, and head and neck squamous cell cancer, providing insights into potential therapeutic strategies.