Proteolytic Processing Converts the Repelling Signal Sema3E into an Inducer of Invasive Growth and Lung Metastasis

TLDR

Sema3E, a repulsive axon‑guidance cue, has been linked to lung metastasis in murine adenocarcinoma models. The study aimed to establish SEMA3E’s relevance in human breast cancer and to characterize its biological activities that promote tumor progression and metastasis. Furin‑dependent proteolytic processing converts full‑length Sema3E into a p61‑Sema3E isoform, which is both required and sufficient for lung‑metastatic activity, cell migration, invasive growth, and ERK1/2 activation in endothelial cells. Expression of Sema3E in mammary adenocarcinoma cells drives experimental lung metastasis, enhances endothelial cell migration and growth, and the p61‑Sema3E isoform reveals a novel growth‑promoting function for a class 3 semaphorin.

Abstract

We have previously shown that the expression of a semaphorin, known as a repelling cue in axon guidance, Sema3E, correlates with the ability to form lung metastasis in murine adenocarcinoma cell models. Now, besides providing evidence for the relevance of SEMA3E to human disease by showing that SEMA3E is frequently expressed in human cancer cell lines and solid tumors from breast cancer patients, we show biological activities of Sema3E, which support the implication of Sema3E in tumor progression and metastasis. In vivo, expression of Sema3E in mammary adenocarcinoma cells induces the ability to form experimental lung metastasis, and in vitro, the Sema3E protein exhibits both migration and growth promoting activity on endothelial cells and pheochromocytoma cells. This represents the first evidence of a metastasis-promoting function of a class 3 semaphorin, as this class of genes has hitherto been implicated in tumor biology only as tumor suppressors and negative regulators of growth. Moreover, we show that the full-size Sema3E protein is converted into a p61-Sema3E isoform due to furin-dependent processing, and by analyzing processing-deficient and truncated forms, we show that the generation of p61-Sema3E is required and sufficient for the function of Sema3E in lung metastasis, cell migration, invasive growth, and extracellular signal-regulated kinase 1/2 activation of endothelial cells. These findings suggest that certain breast cancer cells may increase their lung-colonizing ability by converting the growth repellent, Sema3E, into a growth attractant and point to a type of semaphorin signaling different from the conventional signaling induced by full-size dimeric class 3 semaphorins.