# LCN2 promotes focal adhesion formation and invasion by stimulating c-Src activation

## TL;DR

LCN2 promotes cancer cell invasion by forming focal adhesions and activating c-Src, independent of iron binding.

## Contribution

LCN2 stimulates focal adhesion formation and c-Src activation via ETS1 and PTP1B, revealing a novel iron-independent mechanism.

## Key findings

- LCN2 promotes focal adhesion formation independently of iron binding.
- LCN2 activates c-Src through ETS1 and PTP1B upregulation.
- These findings suggest c-Src inhibitors may treat invasive colorectal cancer.

## Abstract

Previous work has demonstrated that lipocalin2 (LCN2) expression promotes invasion and migration in multiple tumor types. The mechanisms by which LCN2 promotes invasion and migration remain unclear. Previous work from our laboratory demonstrated that LCN2 promotes actin filament formation by inhibiting actin glutathionylation. In this study, we demonstrate that, in addition to inhibiting actin glutathionylation, LCN2 stimulates invasion by promoting the formation of focal adhesions, which is independent of the ability of LCN2 to bind iron (Fe3+). We showed that LCN2 promotes focal adhesion formation by promoting the activation of c-Src (also known as SRC) by stimulating expression of the transcription factor ETS1. ETS1, in turn, upregulates expression of the protein phosphatase PTP1B, resulting in the auto-activation of c-Src and increased paxillin phosphorylation, leading to focal adhesion formation. These results demonstrate that LCN2 has iron-dependent and -independent functions in promoting invasion and highlight the multiple mechanisms by which LCN2 promotes invasion, suggesting that c-Src inhibitors could be used to treat invasive colorectal cancer.

Summary: Expression of LCN2 is elevated in invasive colorectal cancer. We demonstrate that LCN2 promotes invasion by stimulating the formation of focal adhesions by promoting c-Src activation.