TM9SF1 inhibits colorectal cancer metastasis by targeting Vimentin for Tollip-mediated selective autophagic degradation.

Selective autophagy is a finely regulated degradation pathway that can either promote or suppress cancer progression depending on its specific target cargoes. In this study, we report that transmembrane 9 superfamily member 1 (TM9SF1) suppresses colorectal cancer metastasis via selective autophagic degradation of Vimentin. Tm9sf1 knockout significantly increases tumor numbers and size, as well as enhances tumor invasion in colorectal cancer model. In vitro and in vivo phenotypical analyses reveal that TM9SF1 functions as a metastasis suppressor in colorectal cancer. Mechanistically, TM9SF1 facilitates the K63-linked ubiquitination of Vimentin by the E3 ligase TRIM21. The K63-linked ubiquitination of Vimentin serves as a recognition signal for autophagic degradation mediated by autophagic cargo receptor Tollip. Consequently, the downregulation of Vimentin results in a decreased number of F-actin-rich stress fibers and filopodium-like protrusions, ultimately inhibiting colorectal cancer metastasis. Moreover, TM9SF1 is downregulated in colorectal cancer patients with advanced stage compared to those with early stage and associated with favorable prognosis. Overall, our findings identify a novel TM9SF1-TRIM21-Vimentin-Tollip pathway involved in colorectal cancer metastasis, which may provide promising therapeutic targets for the treatment of metastatic colorectal cancer.