Fgfr4, the fibroblast growth factor receptor 4, is a receptor tyrosine kinase. It is involved in the fibroblast growth factor (FGF) signaling pathway, which plays crucial roles in cell survival, proliferation, migration, and angiogenesis [4]. Dysregulation of Fgfr4 signaling has been implicated in oncogenesis, tumor progression, and resistance to anti-tumor therapy in multiple cancers, making it an important gene for cancer research [4].

In hepatocellular carcinoma (HCC), FGF19/Fgfr4 jointly upregulates ETV4 expression through the ERK1/2 pathway, and ETV4 upregulates Fgfr4 expression, creating a positive feedback loop that facilitates HCC metastasis by upregulating PD-L1 and CCL2 [1]. In breast cancer, Fgfr4 may participate in subtype switching from luminal A to HER2-enriched subtype metastases, and its genomic signatures can predict overall survival and site-specific metastasis [2]. In rhabdomyosarcoma, Fgfr4 is highly expressed in tumors and lowly in healthy tissues, making it a potential target for chimeric antigen receptor T-cell therapy [3]. In colorectal cancer, FGF19-mediated ELF4 overexpression promotes metastasis by transactivating Fgfr4 and SRC, and the combination of Fgfr4 and SRC inhibitors suppresses this metastasis [5]. In HCC, KDM6A promotes HCC progression by upregulating Fgfr4 expression, and knockdown of KDM6A inhibits lenvatinib therapy efficacy, indicating KDM6A-Fgfr4 axis importance in HCC treatment [6].

In conclusion, Fgfr4 is a key player in the FGF signaling pathway, with its dysregulation being associated with various cancers. Studies, especially in cancer models, have revealed its role in tumor metastasis, subtype differentiation, and as a potential therapeutic target. Understanding Fgfr4 through these models provides insights into cancer mechanisms and possible treatment strategies.

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. 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/

3. 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/

4. 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/

5. 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/

6. 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/