Fibroblast growth factor signals drive the metastatic behavior in small cell lung cancer

TL;DR

This study identifies fibroblast growth factor signaling as a key driver of metastasis in a specific subtype of small cell lung cancer.

Contribution

The study reveals that the FGF/R axis is a novel driver of metastasis in YAP1-dominant small cell lung cancer.

Findings

Sprouter SCLC cells with YAP1 dominance show increased migration and invasion capabilities.

Blocking the FGF/R axis significantly reduces invasive sprouting in vitro and in vivo.

FGF2 stimulation increases invasive sprouting in YAP1-dominant SCLC cells.

Abstract

Early metastatic spread represents a challenge in fighting small cell lung cancer (SCLC). The molecular mechanisms underlying metastatic dissemination remain unclear in this devastating disease.

Invasive traits were investigated in 13 SCLC cell lines using 3D-spheroid formation, sprouting assays, co-cultures and a zebrafish xenograft model. Proteomic analysis was performed to unravel metastatic drivers, which were validated by qPCR, growth factor arrays and specific inhibitors.

Overall, 8 cell lines formed spheroids, and half of these displayed invasive sprouting in collagen. The ‘sprouter’ SCLC cells, which all had a YAP1-dominant subtype, showed increased migration in zebrafish larvae and penetrated endothelial cell monolayers to a higher extent, thereby mimicking intra- and extravasation. Proteomics revealed differences in adhesion properties, oncogenic pathways and receptor tyrosine kinase signalling. Sprouter cells showed higher expression levels of mesenchymal cell state markers. Stimulation with fibroblast growth factor 2 (FGF2) further induced invasive sprouting, while blocking the FGF/R axis resulted in a significant reduction of sprouting in vitro and in vivo.

The FGF/R axis is a key driver of SCLC metastatic spread in the YAP1-dominant subtype. These data might facilitate the development of potential future therapies targeting FGF/R signalling to prevent SCLC progression and metastasis.

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