Tm4sf1, also known as Transmembrane 4 L six family member 1, is a member of the L6 family and functions as a signal transducer. Physiologically, it is involved in regulating tissue differentiation, signal transduction pathways, cellular activation, proliferation, motility, adhesion, and angiogenesis [6]. It has been implicated in multiple signaling pathways such as the Wnt/β-catenin/SOX2 pathway [1], the TM4SF1/integrin α6/FAK axis [2], and the NOTCH pathway [4]. It is of great biological importance, especially in the context of cancer and certain cardiovascular diseases [1-5, 7-10]. Genetic models, including gene knockout (KO) and conditional knockout (CKO) mouse models, are valuable for studying its functions.

In colorectal cancer, knockdown of Tm4sf1 in SW480 and LoVo cells inhibited migration, invasion, tumour sphere formation, and TGF-β1-mediated EMT, and depletion of Tm4sf1 in a xenograft mouse model inhibited metastasis and tumour growth, revealing its role in maintaining cancer cell stemness and EMT via the Wnt/β-catenin/c-Myc/SOX2 axis [1]. In esophageal squamous cell carcinoma, inhibiting FAK or knocking down Tm4sf1 attenuated cell migration and lung metastasis, indicating its role in promoting metastasis through the TM4SF1/integrin α6/FAK axis [2]. In glioma, silencing Tm4sf1 by RNA interference inhibited cell proliferation, migration, invasion, induced cell cycle arrest and early apoptosis [3]. In hepatocellular carcinoma, knockdown of Tm4sf1 suppressed proliferation in vitro and in vivo, induced non-secretory senescence, and targeting Tm4sf1 via adeno-associated virus induced tumour senescence and enhanced the efficacy of anti-PD-1 therapy [5].

In conclusion, Tm4sf1 plays crucial roles in processes like cancer cell stemness, EMT, metastasis, and proliferation in various cancers including colorectal, esophageal, glioma, and hepatocellular carcinoma. Model-based research, especially KO/CKO mouse models, has significantly contributed to understanding its role in these disease areas, highlighting its potential as a therapeutic target.

References:

1. Tang, Qiang, Chen, Jinhuang, Di, Ziyang, Shu, Xiaogang, Di, Maojun. 2020. TM4SF1 promotes EMT and cancer stemness via the Wnt/β-catenin/SOX2 pathway in colorectal cancer. In Journal of experimental & clinical cancer research : CR, 39, 232. doi:10.1186/s13046-020-01690-z. https://pubmed.ncbi.nlm.nih.gov/33153498/

2. Hou, Sicong, Hao, Xin, Li, Jiajia, Gu, Jianguo, Hang, Qinglei. 2022. TM4SF1 promotes esophageal squamous cell carcinoma metastasis by interacting with integrin α6. In Cell death & disease, 13, 609. doi:10.1038/s41419-022-05067-2. https://pubmed.ncbi.nlm.nih.gov/35835740/

3. Zheng, Yan-Wen, Wang, Man, Zhong, Zhao-Min, Chen, Li-Li, Li, Ming. 2022. TM4SF1 promotes glioma malignancy through multiple mechanisms. In Neoplasma, 69, 859-867. doi:10.4149/neo_2022_211009N1427. https://pubmed.ncbi.nlm.nih.gov/35532297/

4. Yang, Si-Bo, Zhou, Zi-Han, Lei, Jin, Ge, Yu-Zhen, Zuo, Shi. 2023. TM4SF1 upregulates MYH9 to activate the NOTCH pathway to promote cancer stemness and lenvatinib resistance in HCC. In Biology direct, 18, 18. doi:10.1186/s13062-023-00376-8. https://pubmed.ncbi.nlm.nih.gov/37069693/

5. Zeng, Weifeng, Liu, Furong, Liu, Yachong, Liao, Zhibin, Zhang, Zhanguo. 2024. Targeting TM4SF1 promotes tumor senescence enhancing CD8+ T cell cytotoxic function in hepatocellular carcinoma. In Clinical and molecular hepatology, 31, 489-508. doi:10.3350/cmh.2024.0934. https://pubmed.ncbi.nlm.nih.gov/39736265/

6. Rahim, Nur Syafiqah, Wu, Yuan Seng, Sim, Maw Shin, Sekar, Mahendran, Guad, Rhanye Mac. 2023. Three Members of Transmembrane-4-Superfamily, TM4SF1, TM4SF4, and TM4SF5, as Emerging Anticancer Molecular Targets against Cancer Phenotypes and Chemoresistance. In Pharmaceuticals (Basel, Switzerland), 16, . doi:10.3390/ph16010110. https://pubmed.ncbi.nlm.nih.gov/36678607/