LPP is a Src substrate required for invadopodia formation and efficient breast cancer lung metastasis

Elaine Ngan,Peter M Siegel,Jessica Common,John D Lewis,William J Muller,Konstantin Stoletov,Harvey W Smith

doi:10.1038/ncomms15059

Abstract

We have previously shown that lipoma preferred partner (LPP) mediates TGFβ-induced breast cancer cell migration and invasion. Herein, we demonstrate that diminished LPP expression reduces circulating tumour cell numbers, impairs cancer cell extravasation and diminishes lung metastasis. LPP localizes to invadopodia, along with Tks5/actin, at sites of matrix degradation and at the tips of extravasating breast cancer cells as revealed by intravital imaging of the chick chorioallantoic membrane (CAM). Invadopodia formation, breast cancer cell extravasation and metastasis require an intact LPP LIM domain and the ability of LPP to interact with α-actinin. Finally, we show that Src-mediated LPP phosphorylation at specific tyrosine residues (Y245/301/302) is critical for invadopodia formation, breast cancer cell invasion and metastasis. Together, these data define a previously unknown function for LPP in the formation of invadopodia and reveal a requirement for LPP in mediating the metastatic ability of breast cancer cells.

Highlights

We have previously shown that lipoma preferred partner (LPP) mediates TGFb-induced breast cancer cell migration and invasion
We previously demonstrated that LPP promotes the in vitro migration and invasion of breast cancer cells following a TGFb-induced EMT17
To assess the requirement of LPP for breast cancer metastasis in vivo, we stably reduced LPP expression levels in NMuMG-ErbB2 cells and the NIC breast cancer model, which was derived from an ErbB2-expressing mammary tumour that arose in transgenic mice expressing an activated form of ErbB2

Summary

Introduction

We have previously shown that lipoma preferred partner (LPP) mediates TGFb-induced breast cancer cell migration and invasion. Invadopodia are critical structures employed by cancer cells to intravasate into the bloodstream and extravasate into secondary sites during the metastatic process[1] They are located on the ventral side of invading cancer cells and are rich in actin-containing complexes that include: WASP, Arp2/3, Cortactin, Tks4/5 and c-Src (refs 2–7). Inhibition of these structures significantly diminishes tumour cell extravasation and the formation of breast cancer metastases[13,14] In this regard, TGFb promotes Src-induced invadopodia formation via Hic-5 upregulation, while knockdown of Twist[1], a central mediator of EMT, abrogates their formation[15,16]. We delineate an important role for LPP as a Src substrate, a positive regulator of invadopodia formation and an enhancer of breast cancer metastasis

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Conclusion