TSPAN6, a tetraspanin protein, plays diverse roles in biological processes. It is involved in pathways such as EGFR-RAS signaling, STAT3 signaling, and LXR-dependent immune-related pathways. Its functions span from regulating epithelial cell identity to influencing tumor microenvironment and exosome secretion, making it of great biological importance. Genetic models, especially KO/CKO mouse models, are valuable for studying its functions [1,2,3,4].

In Ras-driven epithelial cancers, whole-body knockout and tumor cell autonomous inactivation of Tspan6 in mice enhanced KrasG12D-driven lung tumor initiation and progression. Mechanistically, TSPAN6 binds to EGFR and blocks EGFR-induced RAS activation. Also, its inactivation induces epithelial-to-mesenchymal transition and inhibits cell migration [1]. In glioblastoma, TSPAN6 promoted malignant progression via interacting with CDK5RAP3 and regulating STAT3 signaling pathway, and high-expressing patients had shorter survival [2]. In breast cancer, Tspan6 stimulated the chemoattractive potential of breast cancer cells for B cells in an EV-and LXR-dependent manner [3]. In colorectal cancer, deletion of Tspan6 in Apcmin/+ mice increased adenoma formation and tumor size through activation of EGF-dependent signaling pathways [5].

In conclusion, TSPAN6 is a crucial regulator in multiple biological processes and disease conditions. Model-based research, especially using KO/CKO mouse models, has revealed its significant roles in cancer development, including lung, glioblastoma, breast, and colorectal cancers. These findings enhance our understanding of TSPAN6's functions and its potential as a therapeutic target and biomarker.