Research ArticleCancer

Reverse signaling by semaphorin 4C elicits SMAD1/5- and ID1/3-dependent invasive reprogramming in cancer cells

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Science Signaling  20 Aug 2019:
Vol. 12, Issue 595, eaav2041
DOI: 10.1126/scisignal.aav2041

Semaphorins in reverse

Members of the large family of semaphorins guide cell migration. As ligands, some semaphorins are implicated in promoting cancer progression and angiogenesis. Gurrapu et al. found an alternative mechanism in which semaphorin 4C (Sema4C) acts as a receptor to promote metastasis. In response to interaction with the extracellular domain of PlexinB2 (which is a receptor when Sema4C acts as a ligand), transmembrane-resident Sema4C intracellularly interacted with and activated TGF-β receptors in invasive breast cancer cell lines. Subsequent changes in gene expression suppressed mesenchymal features and promoted metastasis in a mouse model of disseminated-cell seeding and growth. These findings reveal one way in which Sema4C promotes the cellular plasticity necessary for metastatic disease.

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