FGFR4 regulates tumor subtype differentiation in luminal breast cancer and metastatic disease
Susana Garcia-Recio, … , Aleix Prat, Charles M. Perou
Susana Garcia-Recio, … , Aleix Prat, Charles M. Perou
Published June 23, 2020
Citation Information: J Clin Invest. 2020;130(9):4871-4887. https://doi.org/10.1172/JCI130323.
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Research Article Genetics Oncology

FGFR4 regulates tumor subtype differentiation in luminal breast cancer and metastatic disease

Abstract

Mechanisms driving tumor progression from less aggressive subtypes to more aggressive states represent key targets for therapy. We identified a subset of luminal A primary breast tumors that give rise to HER2-enriched (HER2E) subtype metastases, but remain clinically HER2 negative (cHER2–). By testing the unique genetic and transcriptomic features of these cases, we developed the hypothesis that FGFR4 likely participates in this subtype switching. To evaluate this, we developed 2 FGFR4 genomic signatures using a patient-derived xenograft (PDX) model treated with an FGFR4 inhibitor, which inhibited PDX growth in vivo. Bulk tumor gene expression analysis and single-cell RNA sequencing demonstrated that the inhibition of FGFR4 signaling caused molecular switching. In the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) breast cancer cohort, FGFR4-induced and FGFR4-repressed signatures each predicted overall survival. Additionally, the FGFR4-induced signature was an independent prognostic factor beyond subtype and stage. Supervised analysis of 77 primary tumors with paired metastases revealed that the FGFR4-induced signature was significantly higher in luminal/ER+ tumor metastases compared with their primaries. Finally, multivariate analysis demonstrated that the FGFR4-induced signature also predicted site-specific metastasis for lung, liver, and brain, but not for bone or lymph nodes. These data identify a link between FGFR4-regulated genes and metastasis, suggesting treatment options for FGFR4-positive patients, whose high expression is not caused by mutation or amplification.

Authors

Susana Garcia-Recio, Aatish Thennavan, Michael P. East, Joel S. Parker, Juan M. Cejalvo, Joseph P. Garay, Daniel P. Hollern, Xiaping He, Kevin R. Mott, Patricia Galván, Cheng Fan, Sara R. Selitsky, Alisha R. Coffey, David Marron, Fara Brasó-Maristany, Octavio Burgués, Joan Albanell, Federico Rojo, Ana Lluch, Eduardo Martinez de Dueñas, Jeffery M. Rosen, Gary L. Johnson, Lisa A. Carey, Aleix Prat, Charles M. Perou

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Figure 4

Single-cell RNA sequencing of WHIM11 tumor treated with BLU9931 and drug released.

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Single-cell RNA sequencing of WHIM11 tumor treated with BLU9931 and drug...
(A) Left panel: Uniform manifold approximation and projection (UMAP) plot of all combined cells (30,058 cells in total) that passed quality checks in untreated WHIM11 (n = 2; 9298 cells), treated with BLU9931 (n = 2; 9777 cells) (0.6 g/kg/day) for 14 days, and treated but released of drug for 18 days (n = 2; 10,983 cells). Cells and clusters are color coded by each cell population found. Right panel: Heatmap of significantly differentially expressed genes and main Gene Ontology annotations for each cluster in WHIM11 based on MSigDB. Significant genes were identified by Wilcoxon’s signed-rank t test. (B) UMAP plot of all the cells that passed quality checks in WHIM11 and divided by each experimental condition as untreated, treated with BLU9931 (0.6 g/kg/day) for 14 days, and treated but released of drug for 18 days. Cells and clusters are color coded by each cell population found. (D, F, and H) UMAP plots showing the expression of FGFR4, ERBB2, and ESR1 genes across all WHIM11 clusters in WHIM11 untreated, treated with BLU9931 (0.6 g/kg/day) for 14 days, and treated but released of drug for 18 days. (C, E, G, and I) UMAP plots showing the gene signature score (average values of genes present in each score respectively for each cell) of FGFR4-induced signature, FGFR4-repressed signature, proliferation signature, and luminal tumor score (LTS) across all WHIM11 clusters in WHIM11 untreated, treated with BLU9931 (0.6 g/kg/day) for 14 days, and treated but released of drug for 18 days.