Fgfr4, fibroblast growth factor receptor 4, is a receptor tyrosine kinase. It is involved in key biological processes such as cell survival, proliferation, migration, and angiogenesis, mainly through its associated fibroblast growth factor (FGF) signaling pathway [5]. Genetic models like gene knockout (KO) or conditional knockout (CKO) mouse models are valuable for studying its functions.

In hepatocellular carcinoma (HCC), FGF19/Fgfr4 jointly upregulate ETV4 expression through the ERK1/2 pathway, creating a FGF19-ETV4-Fgfr4 positive feedback loop that facilitates metastasis. Inhibition of Fgfr4 can decrease ETV4-enhanced HCC metastasis [1]. In HER2-positive breast cancer, FGFR4 inhibition enhances susceptibility to anti-HER2 therapy by triggering ferroptosis, an iron-dependent oxidative cell death [2]. In luminal breast cancer, inhibition of Fgfr4 signaling causes molecular subtype switching, and FGFR4-induced and FGFR4-repressed signatures predict overall survival and site-specific metastasis [3]. In rhabdomyosarcoma, FGFR4-targeting chimeric antigen receptor (CAR) T-cell therapy shows potential as an effective treatment [4]. In colorectal cancer, ELF4 promotes metastasis by transactivating FGFR4, and the combination of FGFR4 and SRC inhibitors suppresses ELF4-mediated metastasis [6]. In HCC, KDM6A promotes progression by upregulating FGFR4 expression and influences lenvatinib efficacy [7].

In conclusion, Fgfr4 is crucial in multiple biological processes and diseases, especially in cancer. Studies using KO/CKO mouse models or other loss-of-function experiments have revealed its role in tumor metastasis, treatment resistance, and subtype differentiation in various cancers, providing potential therapeutic targets for these diseases.

References:

1. Xie, Meng, Lin, Zhuoying, Ji, Xiaoyu, Huang, Wenjie, Xia, Limin. 2023. FGF19/FGFR4-mediated elevation of ETV4 facilitates hepatocellular carcinoma metastasis by upregulating PD-L1 and CCL2. In Journal of hepatology, 79, 109-125. doi:10.1016/j.jhep.2023.02.036. https://pubmed.ncbi.nlm.nih.gov/36907560/

2. Zou, Yutian, Zheng, Shaoquan, Xie, Xinhua, Tang, Hailin, Xie, Xiaoming. 2022. N6-methyladenosine regulated FGFR4 attenuates ferroptotic cell death in recalcitrant HER2-positive breast cancer. In Nature communications, 13, 2672. doi:10.1038/s41467-022-30217-7. https://pubmed.ncbi.nlm.nih.gov/35562334/

3. Garcia-Recio, Susana, Thennavan, Aatish, East, Michael P, Prat, Aleix, Perou, Charles M. . FGFR4 regulates tumor subtype differentiation in luminal breast cancer and metastatic disease. In The Journal of clinical investigation, 130, 4871-4887. doi:10.1172/JCI130323. https://pubmed.ncbi.nlm.nih.gov/32573490/

4. Tian, Meijie, Wei, Jun S, Shivaprasad, Nityashree, Cheuk, Adam T, Khan, Javed. 2023. Preclinical development of a chimeric antigen receptor T cell therapy targeting FGFR4 in rhabdomyosarcoma. In Cell reports. Medicine, 4, 101212. doi:10.1016/j.xcrm.2023.101212. https://pubmed.ncbi.nlm.nih.gov/37774704/

5. Levine, Kevin M, Ding, Kai, Chen, Lyuqin, Oesterreich, Steffi. 2020. FGFR4: A promising therapeutic target for breast cancer and other solid tumors. In Pharmacology & therapeutics, 214, 107590. doi:10.1016/j.pharmthera.2020.107590. https://pubmed.ncbi.nlm.nih.gov/32492514/

6. Chen, Xilang, Chen, Jie, Feng, Weibo, Wu, Kaichun, Xia, Limin. 2023. FGF19-mediated ELF4 overexpression promotes colorectal cancer metastasis through transactivating FGFR4 and SRC. In Theranostics, 13, 1401-1418. doi:10.7150/thno.82269. https://pubmed.ncbi.nlm.nih.gov/36923538/

7. Guo, Wenyun, Li, Songling, Qian, Yifei, Gao, Wei-Qiang, Liu, Yanfeng. . KDM6A promotes hepatocellular carcinoma progression and dictates lenvatinib efficacy by upregulating FGFR4 expression. In Clinical and translational medicine, 13, e1452. doi:10.1002/ctm2.1452. https://pubmed.ncbi.nlm.nih.gov/37846441/