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In vitro models of the crosstalk between multiple myeloma and stromal cells recapitulate the mild NF-κB activation observed in vivo.
- Source :
-
Cell death & disease [Cell Death Dis] 2024 Oct 06; Vol. 15 (10), pp. 731. Date of Electronic Publication: 2024 Oct 06. - Publication Year :
- 2024
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Abstract
- Multiple myeloma (MM) is linked to chronic NF-κB activity in myeloma cells, but this activity is generally considered a cell-autonomous property of the cancer cells. The precise extent of NF-κB activation and the contributions of the physical microenvironment and of cell-to-cell communications remain largely unknown. By quantitative immunofluorescence, we found that NF-κB is mildly and heterogeneously activated in a fraction of MM cells in human BMs, while only a minority of MM cells shows a strong activation. To gain quantitative insights on NF-κB activation in living MM cells, we combined advanced live imaging of endogenous p65 Venus-knocked-in in MM.1S and HS-5 cell lines to model MM and mesenchymal stromal cells (MSCs), cell co-cultures, microfluidics and custom microbioreactors to mimic the 3D-interactions within the bone marrow (BM) microenvironment. We found that i) reciprocal MM-MSC paracrine crosstalk and cell-to-scaffold interactions shape the inflammatory response in the BM; ii) the pro-inflammatory cytokine IL-1β, abundant in MM patients' plasma, activates MSCs, whose paracrine signals are responsible for strong NF-κB activation in a minority of MM cells; iii) IL-1β, but not TNF-α, activates NF-κB in vivo in BM-engrafted MM cells, while its receptor inhibitor Anakinra reduces the global NF-κB activation. We propose that NF-κB activation in the BM of MM patients is mild, restricted to a minority of cells and modulated by the interplay of restraining physical microenvironmental cues and activating IL-1β-dependent stroma-to-MM crosstalk.<br /> (© 2024. The Author(s).)
- Subjects :
- Humans
Cell Line, Tumor
Interleukin-1beta metabolism
Tumor Microenvironment
Cell Communication
Stromal Cells metabolism
Stromal Cells pathology
Paracrine Communication
Signal Transduction
Transcription Factor RelA metabolism
Multiple Myeloma metabolism
Multiple Myeloma pathology
Multiple Myeloma genetics
Mesenchymal Stem Cells metabolism
NF-kappa B metabolism
Coculture Techniques
Subjects
Details
- Language :
- English
- ISSN :
- 2041-4889
- Volume :
- 15
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Cell death & disease
- Publication Type :
- Academic Journal
- Accession number :
- 39370432
- Full Text :
- https://doi.org/10.1038/s41419-024-07038-1