2. Academic Validation
  3. Fibroblast growth factor signals drive the metastatic behavior in small cell lung cancer

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

  • Br J Cancer. 2025 Dec 13. doi: 10.1038/s41416-025-03276-y.
Büsra Ernhofer # 1 2,  Anna Solta # 1 2,  Julia Sinner # 1 2,  Zsolt Megyesfalvi 1 2 3 4,  Abigail J Deloria 1 2,  Kristiina Boettiger 1 2,  Lisa Glatt 1 2,  Lilla Horvath 3,  Caterina Sturtzel 5 6,  Andrea Wenninger-Weinzierl 5,  Martin Distel 5 6 7,  Michael Grusch 8,  Beata Szeitz 3,  Melinda Rezeli 9 10,  Clemens Aigner 1 2,  Balazs Dome 11 12 13 14 15,  Karin Schelch 16 17
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
  • 2 Comprehensive Center for Chest Diseases, Medical University of Vienna, Vienna, Austria.
  • 3 National Koranyi Institute of Pulmonology, Budapest, Hungary.
  • 4 Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary.
  • 5 St. Anna Children's Cancer Research Institute, Innovative Cancer Models, Vienna, Austria.
  • 6 St. Anna Children's Cancer Research Institute, Zebrafish Platform Austria for Preclinical Drug Screening, (ZANDR), Vienna, Austria.
  • 7 Division of Pediatric Hematology and Oncology, Intermountain Primary Children's Hospital, Huntsman Cancer Institute, Spencer Fox Eccles School of Medicine at the University of Utah, Salt Lake City, UT, USA.
  • 8 Center for Cancer Research, Medical University of Vienna, Vienna, Austria.
  • 9 Department of Biomedical Engineering, Lund University, Lund, Sweden.
  • 10 BioMS - Swedish National Infrastructure for Biological Mass Spectrometry, Lund University, Lund, Sweden.
  • 11 Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. [email protected].
  • 12 Comprehensive Center for Chest Diseases, Medical University of Vienna, Vienna, Austria. [email protected].
  • 13 National Koranyi Institute of Pulmonology, Budapest, Hungary. [email protected].
  • 14 Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary. [email protected].
  • 15 Department of Translational Medicine, Lund University, Lund, Sweden. [email protected].
  • 16 Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. [email protected].
  • 17 Comprehensive Center for Chest Diseases, Medical University of Vienna, Vienna, Austria. [email protected].
  • # Contributed equally.
PMID: 41390896 DOI: 10.1038/s41416-025-03276-y
Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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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