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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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).
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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.
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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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