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

doi:10.1016/j.celrep.2022.110584

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

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Abstract

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.

Original language	English
Article number	110584
Journal	Cell Reports
Volume	39
Issue number	1
DOIs	https://doi.org/10.1016/j.celrep.2022.110584
Publication status	Published - 5 Apr 2022
Externally published	Yes

Bibliographical note

Funding Information:
We thank N. Bovenschen, M. Hadders, B. Levin, K. Shokat, R. Schackmann, I. Ivanova, and S. Boogaard for the experimental support. Also, we thank the Dutch Breast Cancer Research Group (BOOG) for providing clinical data from the BOOG 2005-02 MATADOR study. This research was supported by KWF Kankerbestrijding ( UU2014-7201 ), the Dutch Research Council TOP grant ( NWO-TOP 02007 ), and the European Union’s Horizon 2020 FET Proactive program under grant agreement no. 731957 (MECHANO-CONTROL).

Publisher Copyright:
© 2022 The Authors

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Tavares, S., Liv, N., Pasolli, M., Opdam, M., Rätze, M. A. K., Saornil, M., Sluimer, L. M., Hengeveld, R. C. C., van Es, R., van Werkhoven, E., Vos, H., Rehmann, H., Burgering, B. M. T., Oosterkamp, H. M., Lens, S. M. A., Klumperman, J., Linn, S. C., & Derksen, P. W. B. (2022). FER regulates endosomal recycling and is a predictor for adjuvant taxane benefit in breast cancer. Cell Reports, 39(1), Article 110584. https://doi.org/10.1016/j.celrep.2022.110584

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title = "FER regulates endosomal recycling and is a predictor for adjuvant taxane benefit in breast cancer",

abstract = "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.",

author = "Sandra Tavares and Nalan Liv and Milena Pasolli and Mark Opdam and R{\"a}tze, \{Max A K\} and Manuel Saornil and Sluimer, \{Lilian M\} and Hengeveld, \{Rutger C C\} and \{van Es\}, Robert and \{van Werkhoven\}, Erik and Harmjan Vos and Holger Rehmann and Burgering, \{Boudewijn M T\} and Oosterkamp, \{Hendrika M\} and Lens, \{Susanne M A\} and Judith Klumperman and Linn, \{Sabine C\} and Derksen, \{Patrick W B\}",

note = "Funding Information: We thank N. Bovenschen, M. Hadders, B. Levin, K. Shokat, R. Schackmann, I. Ivanova, and S. Boogaard for the experimental support. Also, we thank the Dutch Breast Cancer Research Group (BOOG) for providing clinical data from the BOOG 2005-02 MATADOR study. This research was supported by KWF Kankerbestrijding ( UU2014-7201 ), the Dutch Research Council TOP grant ( NWO-TOP 02007 ), and the European Union{\textquoteright}s Horizon 2020 FET Proactive program under grant agreement no. 731957 (MECHANO-CONTROL). Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = apr,

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doi = "10.1016/j.celrep.2022.110584",

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Tavares, S, Liv, N, Pasolli, M, Opdam, M, Rätze, MAK, Saornil, M, Sluimer, LM, Hengeveld, RCC, van Es, R, van Werkhoven, E, Vos, H, Rehmann, H, Burgering, BMT, Oosterkamp, HM, Lens, SMA, Klumperman, J, Linn, SC & Derksen, PWB 2022, 'FER regulates endosomal recycling and is a predictor for adjuvant taxane benefit in breast cancer', Cell Reports, vol. 39, no. 1, 110584. https://doi.org/10.1016/j.celrep.2022.110584

TY - JOUR

T1 - FER regulates endosomal recycling and is a predictor for adjuvant taxane benefit in breast cancer

AU - Tavares, Sandra

AU - Liv, Nalan

AU - Pasolli, Milena

AU - Opdam, Mark

AU - Rätze, Max A K

AU - Saornil, Manuel

AU - Sluimer, Lilian M

AU - Hengeveld, Rutger C C

AU - van Es, Robert

AU - van Werkhoven, Erik

AU - Vos, Harmjan

AU - Rehmann, Holger

AU - Burgering, Boudewijn M T

AU - Oosterkamp, Hendrika M

AU - Lens, Susanne M A

AU - Klumperman, Judith

AU - Linn, Sabine C

AU - Derksen, Patrick W B

N1 - Funding Information: We thank N. Bovenschen, M. Hadders, B. Levin, K. Shokat, R. Schackmann, I. Ivanova, and S. Boogaard for the experimental support. Also, we thank the Dutch Breast Cancer Research Group (BOOG) for providing clinical data from the BOOG 2005-02 MATADOR study. This research was supported by KWF Kankerbestrijding ( UU2014-7201 ), the Dutch Research Council TOP grant ( NWO-TOP 02007 ), and the European Union’s Horizon 2020 FET Proactive program under grant agreement no. 731957 (MECHANO-CONTROL). Publisher Copyright: © 2022 The Authors

PY - 2022/4/5

Y1 - 2022/4/5

N2 - 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.

AB - 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.

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U2 - 10.1016/j.celrep.2022.110584

DO - 10.1016/j.celrep.2022.110584

M3 - Article

C2 - 35385742

SN - 2211-1247

VL - 39

JO - Cell Reports

JF - Cell Reports

IS - 1

M1 - 110584

ER -

FER regulates endosomal recycling and is a predictor for adjuvant taxane benefit in breast cancer

Abstract

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