TMEM216 inhibits breast cancer lung metastasis by modulating IGF1R-IRS4 signaling pathway

Breast cancer (BC) metastasis remains a major cause of mortality, yet the molecular mechanisms driving this process are incompletely understood. This study identifies TMEM216, a transmembrane protein implicated in ciliary homeostasis, as a suppressor of lung metastasis in BC. Using mammary-specific Tmem216 knockout mice, we demonstrate that Tmem216 deficiency promotes lung metastasis without affecting primary tumor proliferation. Clinical analyses reveal reduced TMEM216 expression in metastatic lesions and aggressive cell lines, correlating with poor patient distant metastasis-free survival. Mechanistically, TMEM216 interacts with IGF1R and binds to IRS4 via the conserved K79-D1049 interaction, disrupting the IGF1R-IRS4 complex formation and suppressing IGF pathway activation. Rescue experiments in vitro and in vivo confirm that TMEM216-mediated metastasis inhibition depends on IGF signaling modulation. Tissue microarray analyses further establish an inverse correlation between TMEM216 levels and IGF1R phosphorylation in BC patients, with low TMEM216 expression associated with advanced metastasis. These findings delineate TMEM216 as a critical regulator of the IGF1R-IRS4 axis, offering therapeutic opportunities for targeting metastatic BC. The transmembrane protein TMEM216 is known for its role in primary cilia homeostasis. Here the authors find that TMEM216 deficiency promotes breast cancer lung metastasis through activation of the insulin-like growth factor signaling pathway.