A novel vimentin variant from tumor-associated macrophages directs cancer metastasis by engaging IGF-1R

Tumor-associated macrophages (TAMs) are recognized for their role in promoting malignancy. However, the specific mechanisms by which they drive cancer cell migration remain largely unexplored. Here, we identified a novel N-terminal-less variant of vimentin, a cytoskeletal intermediate filament protein, that is selectively secreted by TAMs through a type I unconventional secretion pathway following caspase cleavage of its N-terminus. The macrophage-secreted short vimentin (mssVIM) enhances tumor migration, as demonstrated in breast cancer cell lines, patient-derived cancer cells, mammospheres, and in vivo mouse xenograft models. Mechanistically, mssVIM binds and activates the insulin-like growth factor 1 receptor (IGF-1R) on the cancer cell surface, by exposing binding sites that are otherwise masked in full-length vimentin. Unlike the canonical IGF-1-IGF-1R signaling pathway that promotes cell proliferation, mssVIM-activated IGF-1R triggers ribosomal S6 kinase (RSK) activation, which increases integrin αVβ6 expression, ultimately facilitating tumor cell migration. Analysis of tissue samples from a cohort of breast cancer patients showed that mssVIM levels positively correlate with tumor malignancy and lymph node metastasis, suggesting its potential as a prognostic biomarker.