FER regulates endosomal recycling and is a predictor for adjuvant taxane benefit in breast cancer
Sandra Tavares,
Nalan Liv,
Milena Pasolli,
Mark Opdam,
Max A.K. Rätze,
Manuel Saornil,
Lilian M. Sluimer,
Rutger C.C. Hengeveld,
Robert van Es,
Erik van Werkhoven,
Harmjan Vos,
Holger Rehmann,
Boudewijn M.T. Burgering,
Hendrika M. Oosterkamp,
Susanne M.A. Lens,
Judith Klumperman,
Sabine C. Linn,
Patrick W.B. Derksen
Affiliations
Sandra Tavares
Department of Pathology, University Medical Center Utrecht, 3584CX Utrecht, the Netherlands
Nalan Liv
Section Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, 3584CX Utrecht, the Netherlands
Milena Pasolli
Cell Biology, Neurobiology, and Biophysics, Department of Biology, Faculty of Science, Utrecht University, 3584CH Utrecht, the Netherlands
Mark Opdam
Department of Molecular Pathology, Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands
Max A.K. Rätze
Department of Pathology, University Medical Center Utrecht, 3584CX Utrecht, the Netherlands
Manuel Saornil
Department of Pathology, University Medical Center Utrecht, 3584CX Utrecht, the Netherlands
Lilian M. Sluimer
Department of Pathology, University Medical Center Utrecht, 3584CX Utrecht, the Netherlands
Rutger C.C. Hengeveld
Oncode Institute, Department of Molecular Cancer Research, University Medical Center Utrecht, 3584CX Utrecht, the Netherlands
Robert van Es
Oncode Institute, Department of Molecular Cancer Research, University Medical Center Utrecht, 3584CX Utrecht, the Netherlands
Erik van Werkhoven
Department of Molecular Pathology, Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands
Harmjan Vos
Oncode Institute, Department of Molecular Cancer Research, University Medical Center Utrecht, 3584CX Utrecht, the Netherlands
Holger Rehmann
Flensburg University of Applied Sciences, 24943 Flensburg, Germany
Boudewijn M.T. Burgering
Oncode Institute, Department of Molecular Cancer Research, University Medical Center Utrecht, 3584CX Utrecht, the Netherlands
Hendrika M. Oosterkamp
Department of Medical Oncology, Haaglanden Medisch Centrum, 2501 CK The Hague, the Netherlands
Susanne M.A. Lens
Oncode Institute, Department of Molecular Cancer Research, University Medical Center Utrecht, 3584CX Utrecht, the Netherlands
Judith Klumperman
Section Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, 3584CX Utrecht, the Netherlands
Sabine C. Linn
Department of Pathology, University Medical Center Utrecht, 3584CX Utrecht, the Netherlands; Department of Molecular Pathology, Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands; Department of Medical Oncology, Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands
Patrick W.B. Derksen
Department of Pathology, University Medical Center Utrecht, 3584CX Utrecht, the Netherlands; Corresponding author
Summary: Elevated expression of non-receptor tyrosine kinase FER is an independent prognosticator that correlates with poor survival of high-grade and basal/triple-negative breast cancer (TNBC) patients. Here, we show that high FER levels are also associated with improved outcomes after adjuvant taxane-based combination chemotherapy in high-risk, HER2-negative patients. In TNBC cells, we observe a causal relation between high FER levels and sensitivity to taxanes. Proteomics and mechanistic studies demonstrate that FER regulates endosomal recycling, a microtubule-dependent process that underpins breast cancer cell invasion. Using chemical genetics, we identify DCTN2 as a FER substrate. Our work indicates that the DCTN2 tyrosine 6 is essential for the development of tubular recycling domains in early endosomes and subsequent propagation of TNBC cell invasion in 3D. In conclusion, we show that high FER expression promotes endosomal recycling and represents a candidate predictive marker for the benefit of adjuvant taxane-containing chemotherapy in high-risk patients, including TNBC patients.
