Maldonado, Horacio and Dreger, Marcel and Bedgood, Lara D. and Kyriakou, Theano and Wolanska, Katarzyna I. and Rigby, Megan E. and Marotta, Valeria E. and Webster, Justine M. and Wang, Jun and Rusilowicz-Jones, Emma V. and Marshall, John F. and Coulson, Judy M. and MacPherson, Iain R. and Hurlstone, Adam and Morgan, Mark R. (2024) A trafficking regulatory subnetwork governs α V β 6 integrin-HER2 cross-talk to control breast cancer invasion and drug resistance. Science Advances, 10 (49): eadk9944. ISSN 2375-2548

Abstract

HER2 and αVβ6 integrin are independent predictors of breast cancer survival and metastasis. We identify an αVβ6/HER2 cross-talk mechanism driving invasion, which is dysregulated in drug-resistant HER2+ breast cancer cells. Proteomic analyses reveal ligand-bound αVβ6 recruits HER2 and a trafficking subnetwork, comprising guanosine triphosphatases RAB5 and RAB7A and the Rab regulator guanine nucleotide dissociation inhibitor 2 (GDI2). The RAB5/RAB7A/GDI2 functional module mediates direct cross-talk between αVβ6 and HER2, affecting receptor trafficking and signaling. Acute exposure to trastuzumab increases recruitment of the subnetwork to αVβ6, but trastuzumab resistance decouples GDI2 recruitment. GDI2, RAB5, and RAB7A cooperate to regulate migration and transforming growth factor–β activation to promote invasion. However, these mechanisms are dysregulated in trastuzumab-resistant cells. In patients, RAB5A, RAB7A, and GDI2 expression correlates with patient survival and αVβ6 expression predicts relapse following trastuzumab treatment. Thus, the RAB5/RAB7A/GDI2 subnetwork regulates αVβ6-HER2 cross-talk to drive breast cancer invasion but is subverted in trastuzumab-resistant cells to drive αVβ6-independent and HER2-independent tumor progression.

People
Maldonado, Horacio
Author

Maldonado, Horacio and Dreger, Marcel and Bedgood, Lara D. and Kyriakou, Theano and Wolanska, Katarzyna I. and Rigby, Megan E. and Marotta, Valeria E. and Webster, Justine M. and Wang, Jun and Rusilowicz-Jones, Emma V. and Marshall, John F. and Coulson, Judy M. and MacPherson, Iain R. and Hurlstone, Adam and Morgan, Mark R. (2024) A trafficking regulatory subnetwork governs α V β 6 integrin-HER2 cross-talk to control breast cancer invasion and drug resistance. Science Advances, 10 (49): eadk9944. ISSN 2375-2548

See full publications list
Dreger, Marcel
Author

Maldonado, Horacio and Dreger, Marcel and Bedgood, Lara D. and Kyriakou, Theano and Wolanska, Katarzyna I. and Rigby, Megan E. and Marotta, Valeria E. and Webster, Justine M. and Wang, Jun and Rusilowicz-Jones, Emma V. and Marshall, John F. and Coulson, Judy M. and MacPherson, Iain R. and Hurlstone, Adam and Morgan, Mark R. (2024) A trafficking regulatory subnetwork governs α V β 6 integrin-HER2 cross-talk to control breast cancer invasion and drug resistance. Science Advances, 10 (49): eadk9944. ISSN 2375-2548

See full publications list
Bedgood, Lara D.
Author

Maldonado, Horacio and Dreger, Marcel and Bedgood, Lara D. and Kyriakou, Theano and Wolanska, Katarzyna I. and Rigby, Megan E. and Marotta, Valeria E. and Webster, Justine M. and Wang, Jun and Rusilowicz-Jones, Emma V. and Marshall, John F. and Coulson, Judy M. and MacPherson, Iain R. and Hurlstone, Adam and Morgan, Mark R. (2024) A trafficking regulatory subnetwork governs α V β 6 integrin-HER2 cross-talk to control breast cancer invasion and drug resistance. Science Advances, 10 (49): eadk9944. ISSN 2375-2548

See full publications list
Kyriakou, Theano
Author

Maldonado, Horacio and Dreger, Marcel and Bedgood, Lara D. and Kyriakou, Theano and Wolanska, Katarzyna I. and Rigby, Megan E. and Marotta, Valeria E. and Webster, Justine M. and Wang, Jun and Rusilowicz-Jones, Emma V. and Marshall, John F. and Coulson, Judy M. and MacPherson, Iain R. and Hurlstone, Adam and Morgan, Mark R. (2024) A trafficking regulatory subnetwork governs α V β 6 integrin-HER2 cross-talk to control breast cancer invasion and drug resistance. Science Advances, 10 (49): eadk9944. ISSN 2375-2548

See full publications list
Wolanska, Katarzyna I.
Author

Maldonado, Horacio and Dreger, Marcel and Bedgood, Lara D. and Kyriakou, Theano and Wolanska, Katarzyna I. and Rigby, Megan E. and Marotta, Valeria E. and Webster, Justine M. and Wang, Jun and Rusilowicz-Jones, Emma V. and Marshall, John F. and Coulson, Judy M. and MacPherson, Iain R. and Hurlstone, Adam and Morgan, Mark R. (2024) A trafficking regulatory subnetwork governs α V β 6 integrin-HER2 cross-talk to control breast cancer invasion and drug resistance. Science Advances, 10 (49): eadk9944. ISSN 2375-2548

See full publications list
Rigby, Megan E.
Author

Maldonado, Horacio and Dreger, Marcel and Bedgood, Lara D. and Kyriakou, Theano and Wolanska, Katarzyna I. and Rigby, Megan E. and Marotta, Valeria E. and Webster, Justine M. and Wang, Jun and Rusilowicz-Jones, Emma V. and Marshall, John F. and Coulson, Judy M. and MacPherson, Iain R. and Hurlstone, Adam and Morgan, Mark R. (2024) A trafficking regulatory subnetwork governs α V β 6 integrin-HER2 cross-talk to control breast cancer invasion and drug resistance. Science Advances, 10 (49): eadk9944. ISSN 2375-2548

See full publications list
Marotta, Valeria E.
Author

Maldonado, Horacio and Dreger, Marcel and Bedgood, Lara D. and Kyriakou, Theano and Wolanska, Katarzyna I. and Rigby, Megan E. and Marotta, Valeria E. and Webster, Justine M. and Wang, Jun and Rusilowicz-Jones, Emma V. and Marshall, John F. and Coulson, Judy M. and MacPherson, Iain R. and Hurlstone, Adam and Morgan, Mark R. (2024) A trafficking regulatory subnetwork governs α V β 6 integrin-HER2 cross-talk to control breast cancer invasion and drug resistance. Science Advances, 10 (49): eadk9944. ISSN 2375-2548

See full publications list
Webster, Justine M.
Author

Maldonado, Horacio and Dreger, Marcel and Bedgood, Lara D. and Kyriakou, Theano and Wolanska, Katarzyna I. and Rigby, Megan E. and Marotta, Valeria E. and Webster, Justine M. and Wang, Jun and Rusilowicz-Jones, Emma V. and Marshall, John F. and Coulson, Judy M. and MacPherson, Iain R. and Hurlstone, Adam and Morgan, Mark R. (2024) A trafficking regulatory subnetwork governs α V β 6 integrin-HER2 cross-talk to control breast cancer invasion and drug resistance. Science Advances, 10 (49): eadk9944. ISSN 2375-2548

See full publications list
Wang, Jun
Author
Rusilowicz-Jones, Emma V.
Author

Maldonado, Horacio and Dreger, Marcel and Bedgood, Lara D. and Kyriakou, Theano and Wolanska, Katarzyna I. and Rigby, Megan E. and Marotta, Valeria E. and Webster, Justine M. and Wang, Jun and Rusilowicz-Jones, Emma V. and Marshall, John F. and Coulson, Judy M. and MacPherson, Iain R. and Hurlstone, Adam and Morgan, Mark R. (2024) A trafficking regulatory subnetwork governs α V β 6 integrin-HER2 cross-talk to control breast cancer invasion and drug resistance. Science Advances, 10 (49): eadk9944. ISSN 2375-2548

Glover, Hannah L. and Mendes, Marta and Gomes-Neto, Joana and Rusilowicz-Jones, Emma V. and Rigden, Daniel J. and Dittmar, Gunnar and Urbé, Sylvie and Clague, Michael J. (2024) Microtubule association of TRIM3 revealed by differential extraction proteomics. Journal of Cell Science, 137 (2): jcs261522. ISSN 0021-9533

See full publications list
Marshall, John F.
Author

Maldonado, Horacio and Dreger, Marcel and Bedgood, Lara D. and Kyriakou, Theano and Wolanska, Katarzyna I. and Rigby, Megan E. and Marotta, Valeria E. and Webster, Justine M. and Wang, Jun and Rusilowicz-Jones, Emma V. and Marshall, John F. and Coulson, Judy M. and MacPherson, Iain R. and Hurlstone, Adam and Morgan, Mark R. (2024) A trafficking regulatory subnetwork governs α V β 6 integrin-HER2 cross-talk to control breast cancer invasion and drug resistance. Science Advances, 10 (49): eadk9944. ISSN 2375-2548

See full publications list
Coulson, Judy M.
Author

Maldonado, Horacio and Dreger, Marcel and Bedgood, Lara D. and Kyriakou, Theano and Wolanska, Katarzyna I. and Rigby, Megan E. and Marotta, Valeria E. and Webster, Justine M. and Wang, Jun and Rusilowicz-Jones, Emma V. and Marshall, John F. and Coulson, Judy M. and MacPherson, Iain R. and Hurlstone, Adam and Morgan, Mark R. (2024) A trafficking regulatory subnetwork governs α V β 6 integrin-HER2 cross-talk to control breast cancer invasion and drug resistance. Science Advances, 10 (49): eadk9944. ISSN 2375-2548

See full publications list
Macpherson, Iain R.
Author

Maldonado, Horacio and Dreger, Marcel and Bedgood, Lara D. and Kyriakou, Theano and Wolanska, Katarzyna I. and Rigby, Megan E. and Marotta, Valeria E. and Webster, Justine M. and Wang, Jun and Rusilowicz-Jones, Emma V. and Marshall, John F. and Coulson, Judy M. and MacPherson, Iain R. and Hurlstone, Adam and Morgan, Mark R. (2024) A trafficking regulatory subnetwork governs α V β 6 integrin-HER2 cross-talk to control breast cancer invasion and drug resistance. Science Advances, 10 (49): eadk9944. ISSN 2375-2548

Hanna, Daire and Merrick, Sophie and Ghose, Aruni and Devlin, Michael John and Yang, Dorothy D. and Phillips, Edward and Okines, Alicia and Chopra, Neha and Papadimatraki, Elisavet and ROSS, KIRSTY and MacPherson, Iain and Boh, Zhuang Y. and Michie, Caroline O. and Swampillai, Angela and Gupta, Sunnia and Robinson, Tim and Germain, Lewis and Twelves, Chris and Atkinson, Charlotte and Konstantis, Apostolos and Riddle, Pippa and Cresti, Nicola and Naik, Jay D. and Borley, Annabel and Guppy, Amy and Schmid, Peter and Phillips, Melissa (2024) Real world study of sacituzumab govitecan in metastatic triple-negative breast cancer in the United Kingdom. British Journal of Cancer, 130 (12). pp. 1916-1920. ISSN 0007-0920

Agnew, Sommer and Crawford, Megan and MacPherson, Iain and Shiramizu, Victor and Fleming, Leanne (2024) The impact of symptom clusters on endocrine therapy adherence in patients with breast cancer. Breast, 75: 103731. ISSN 0960-9776

See full publications list
Hurlstone, Adam
Author

Maldonado, Horacio and Dreger, Marcel and Bedgood, Lara D. and Kyriakou, Theano and Wolanska, Katarzyna I. and Rigby, Megan E. and Marotta, Valeria E. and Webster, Justine M. and Wang, Jun and Rusilowicz-Jones, Emma V. and Marshall, John F. and Coulson, Judy M. and MacPherson, Iain R. and Hurlstone, Adam and Morgan, Mark R. (2024) A trafficking regulatory subnetwork governs α V β 6 integrin-HER2 cross-talk to control breast cancer invasion and drug resistance. Science Advances, 10 (49): eadk9944. ISSN 2375-2548

See full publications list
Morgan, Mark R.
Author

Maldonado, Horacio and Dreger, Marcel and Bedgood, Lara D. and Kyriakou, Theano and Wolanska, Katarzyna I. and Rigby, Megan E. and Marotta, Valeria E. and Webster, Justine M. and Wang, Jun and Rusilowicz-Jones, Emma V. and Marshall, John F. and Coulson, Judy M. and MacPherson, Iain R. and Hurlstone, Adam and Morgan, Mark R. (2024) A trafficking regulatory subnetwork governs α V β 6 integrin-HER2 cross-talk to control breast cancer invasion and drug resistance. Science Advances, 10 (49): eadk9944. ISSN 2375-2548

See full publications list
Texts
84:85
lightbox image
343062.pdf - Published Version
Available under License Creative Commons Attribution.

Download (7MB) | Preview
Information
Title:
A trafficking regulatory subnetwork governs α V β 6 integrin-HER2 cross-talk to control breast cancer invasion and drug resistance
Creators:
Maldonado, Horacio and Dreger, Marcel and Bedgood, Lara D. and Kyriakou, Theano and Wolanska, Katarzyna I. and Rigby, Megan E. and Marotta, Valeria E. and Webster, Justine M. and Wang, Jun and Rusilowicz-Jones, Emma V. and Marshall, John F. and Coulson, Judy M. and MacPherson, Iain R. and Hurlstone, Adam and Morgan, Mark R.
Identification Number:
10.1126/sciadv.adk9944
Date:
4 December 2024
Divisions:
College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Publisher:
American Association for the Advancement of Science
Additional Information:
This work was supported by the Breast Cancer Now grant 2015MayPR507 (M.R.M. and H.M.), North West Cancer Research grant CD2019.12 (M.R.M. and H.M), North West Cancer Research grant CR1010 (M.R.M. and K.I.W.), North West Cancer Research grant CR1143 (M.R.M. and K.I.W.), North West Cancer Research grant CEMorgan2018 (M.R.M.), UK Research & Innovation Medical Research Council grant iCASE:SME:MR/R015902/1 (M.R.M. and T.K.), UK Research & Innovation Biotechnology and Biological Sciences Research Council grant BB/T008695/1 (M.R.M. and M.E.R.), Breast Cancer Now grant 2018NovPhD1269 (J.M.C., M.R.M., and V.E.M.), and Christie Charity Fund grant A00092 (A.H. and M.D.).
Library
URI:
https://pub.demo35.eprints-hosting.org/id/eprint/84
Item Type:
Article
Depositing User:
Unnamed user with email ejo1f20@soton.ac.uk
Date Deposited:
11 Jun 2025 16:34
Revision:
14
Last Modified:
12 Jun 2025 12:16
View Item