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RAGE/SNAIL1 signaling drives epithelial-mesenchymal plasticity in metastatic triple-negative breast cancer

Oncogene volume 42, pages 2610–2628 (2023)Cite this article

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Abstract

Epithelial/Mesenchymal (E/M) plasticity plays a fundamental role both in embryogenesis and during tumorigenesis. The receptor for advanced glycation end products (RAGE) is a driver of cell plasticity in fibrotic diseases; however, its role and molecular mechanism in triple-negative breast cancer (TNBC) remains unclear. Here, we demonstrate that RAGE signaling maintains the mesenchymal phenotype of aggressive TNBC cells by enforcing the expression of SNAIL1. Besides, we uncover a crosstalk mechanism between the TGF-β and RAGE pathways that is required for the acquisition of mesenchymal traits in TNBC cells. Consistently, RAGE inhibition elicits epithelial features that block migration and invasion capacities. Next, since RAGE is a sensor of the tumor microenvironment, we modeled acute acidosis in TNBC cells and showed it promotes enhanced production of RAGE ligands and the activation of RAGE-dependent invasive properties. Furthermore, acute acidosis increases SNAIL1 levels and tumor cell invasion in a RAGE-dependent manner. Finally, we demonstrate that in vivo inhibition of RAGE reduces metastasis incidence and expands survival, consistent with molecular effects that support the relevance of RAGE signaling in E/M plasticity. These results uncover new molecular insights on the regulation of E/M phenotypes in cancer metastasis and provide rationale for pharmacological intervention of this signaling axis.

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Fig. 1: RAGE signaling drives cell plasticity and invasion in TNBC cells.
Fig. 2: SNAIL1 is a key downstream effector of the tumor cell plasticity driven by RAGE in TNBC cells.
Fig. 3: RAGE antagonists impair EMT mediated by TGF-β1 in breast cancer cells.
Fig. 4: RAGE antagonists block cell migration, invasion and RAGE oligomerization induced by acidosis.
Fig. 5: SNAIL1 regulates cell migration and invasion induced by acidosis.
Fig. 6: The subcellular localization of RAGE correlates with metastatic incidence.

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Data availability

The RNA-seq data were deposited in the Gene Expression Omnibus with the accession code GSE223229. The mass spectrometry proteomics data was deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD042042. All other data generated and backing the results and conclusions of this study are available from the corresponding author on reasonable request.

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Funding

Authors from VHIO would like to acknowledge the Cellex Foundation for providing research facilities and equipment, the FERO Foundation for their funding support and the Centro de Investigación Biomédica en Red de Cáncer (CIBERONC) from the Institute of Health Carlos III (ISCIII) for their support on this research. JV acknowledges the Project “PI19/01292", funded by Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. Authors from VHIO acknowledge the State Agency for Research (Agencia Estatal de Investigación) the financial support as a Center of Excellence Severo Ochoa (CEX2020-001024-S/AEI/10.13039/ 501100011033).

Author information

Author notes

  1. María Abad

    Present address: Altos Labs Cambridge Institute of Science, Cambridge, UK

Authors and Affiliations

  1. Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain

    Mireia Pujals, Carla Mayans, Chiara Bellio, Olga Méndez, Emanuela Greco, Roberta Fasani, Mercè Alemany-Chavarria, Paolo Nuciforo, Francesc Canals, Lara Nonell, María Abad & Josep Villanueva

  2. Universitat de Barcelona, Barcelona, Spain

    Carla Mayans

  3. Medical Oncology Service, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain

    Esther Zamora, Cristina Saura & Josep Tabernero

  4. Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain

    Esther Zamora & Cristina Saura

  5. LEITAT Technological Center, 08028, Barcelona, Spain

    Laura Padilla & Francesc Mitjans

  6. IOB Institute of Oncology, Quiron Group (Quiron-IOB), Barcelona, Spain

    Josep Tabernero

  7. University of Vic-Central University of Catalonia (UVic-UCC), Barcelona, Spain

    Josep Tabernero

  8. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain

    Josep Tabernero & Josep Villanueva

Authors
  1. Mireia Pujals
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  2. Carla Mayans
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  3. Chiara Bellio
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  4. Olga Méndez
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  5. Emanuela Greco
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  6. Roberta Fasani
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  7. Mercè Alemany-Chavarria
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  8. Esther Zamora
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  9. Laura Padilla
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  10. Francesc Mitjans
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  11. Paolo Nuciforo
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  12. Francesc Canals
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  13. Lara Nonell
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  14. María Abad
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  15. Cristina Saura
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  16. Josep Tabernero
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  17. Josep Villanueva
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Contributions

Conceptualization, MP and JV; Funding acquisition, JT and JV; Investigation, MP, CM, CB and OM; Methodology, MP, CM, EG, MA, RF and FC; Project administration, JV; Resources, EZ, CS, LP, PN and FM; Bioinformatic Analysis, MA-C and LN; Supervision, JV; Validation, MP, CM and JV; Writing – original draft, MP and JV; Writing – review & editing, MP, CM and JV.

Corresponding author

Correspondence to Josep Villanueva.

Ethics declarations

Competing interests

JT reports personal financial interest in form of scientific consultancy role for Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiff Oncology, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna Inc, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seattle Genetics, Servier, Sotio Biotech, Taiho, Tessa Therapeutics, TheraMyc and Tolremo Therapeutics. Stocks: Oniria Therapeutics and also educational collaboration with Imedex/HMP, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education and Physicians Education Resource (PER). PN reports personal financial interest in form of receiving honoraria or consultation fees by Novartis, Bayer, MSD Oncology, Targos Molecular Pathology GmbH. Travel, accommodation paid or reimbursed by Novartis. CS reports personal financial interest serving as consultant, participated in advisory boards or received travel grants from: AstraZeneca, AX'Consulting, Byondis B.V, Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F.Hoffmann-La Roche Ltd, Gilead, Lilly, MediTech, Merck Sharp & Dohme, Novartis, Pfizer, Philips, Pierre Fabre, PintPharma, Puma Biotechnology, SeaGen, Synthon biopharmaceutical and Zymeworks. The other authors declare no competing interests.

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Pujals, M., Mayans, C., Bellio, C. et al. RAGE/SNAIL1 signaling drives epithelial-mesenchymal plasticity in metastatic triple-negative breast cancer. Oncogene 42, 2610–2628 (2023). https://doi.org/10.1038/s41388-023-02778-4

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  • DOI: https://doi.org/10.1038/s41388-023-02778-4

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