Msln-KO Mouse

Msln, also known as Mesothelin, is a glycoprotein. It is considered to play an important role in cell survival, proliferation, and tumor progression [4]. However, the exact associated pathways remain not fully clear. Genetic models are valuable for studying Msln's functions.

In cancer research, Msln has emerged as an attractive target for CAR T-cell therapy of several solid malignancies. In ovarian cancer models, tuning the activation of MSLN-CAR T cells, such as by mutating CD3ζ chain immunoreceptor tyrosine-based activation motifs (ITAMs), can enhance their antitumor responses and persistence [1]. Also, MSLN-CAR T cells can provide antitumor immunity against ovarian cancer, though coinhibitory pathways may impede their persistence in the tumor microenvironment [2]. In pancreatic cancer cells, Msln knockout (KO) leads to decreased adhesion, proliferation, migration, invasion, as well as reduced clone and tumor sphere formation, and increased sensitivity to gemcitabine, indicating that Msln can induce chemoresistance by enhancing certain cell traits [3]. In triple-negative breast cancer, alkalization of the microenvironment can promote the membrane expression of Msln and enhance the killing efficiency of MSLN-CAR-T cells, suggesting that improving Msln target antigen expression can be beneficial for treatment [5].

In conclusion, Msln is closely associated with tumor-related processes, especially in ovarian and pancreatic cancers. Studies using gene knockout models have revealed its role in promoting cancer cell survival, proliferation, and chemoresistance, and have also provided insights into potential therapeutic strategies targeting Msln, such as CAR T-cell therapy.

References:

1. Schoutrop, Esther, Poiret, Thomas, El-Serafi, Ibrahim, Magalhaes, Isabelle, Mattsson, Jonas. . Tuned activation of MSLN-CAR T cells induces superior antitumor responses in ovarian cancer models. In Journal for immunotherapy of cancer, 11, . doi:10.1136/jitc-2022-005691. https://pubmed.ncbi.nlm.nih.gov/36746513/

2. Schoutrop, Esther, El-Serafi, Ibrahim, Poiret, Thomas, Magalhaes, Isabelle, Mattsson, Jonas. 2021. Mesothelin-Specific CAR T Cells Target Ovarian Cancer. In Cancer research, 81, 3022-3035. doi:10.1158/0008-5472.CAN-20-2701. https://pubmed.ncbi.nlm.nih.gov/33795251/

3. Hu, Jili, Wang, Jia, Guo, Xu, Chen, Chaowen, Zhu, Bin. 2024. MSLN induced EMT, cancer stem cell traits and chemotherapy resistance of pancreatic cancer cells. In Heliyon, 10, e29210. doi:10.1016/j.heliyon.2024.e29210. https://pubmed.ncbi.nlm.nih.gov/38628720/

4. Li, Yike, Tian, Wanjia, Zhang, Hong, Lei, Ningjing, Zhang, Weiwei. 2022. MSLN Correlates With Immune Infiltration and Chemoresistance as a Prognostic Biomarker in Ovarian Cancer. In Frontiers in oncology, 12, 830570. doi:10.3389/fonc.2022.830570. https://pubmed.ncbi.nlm.nih.gov/35692779/

5. Wu, Min, Mao, Ling, Zhai, Xuejia, Li, Jianjun, Yu, Shicang. 2024. Microenvironmental alkalization promotes the therapeutic effects of MSLN-CAR-T cells. In Journal for immunotherapy of cancer, 12, . doi:10.1136/jitc-2024-009510. https://pubmed.ncbi.nlm.nih.gov/39433427/