Utilizing 3D Models to Unravel the Dynamics of Myeloma Plasma Cells’ Escape from the Bone Marrow Microenvironment

Verbruggen, Stefaan W.; Freeman, Ciara L.; Freeman, Fiona E.

doi:10.3390/cancers16050889

Cited by 2 publications

References 96 publications

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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

Colombo,

Guzzeloni,

Kizilirmak

et al. 2024

Cell Death Dis

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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.

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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

Colombo,

Guzzeloni,

Kizilirmak

et al. 2024

Cell Death Dis

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Basement membrane hydrogels dampen CAR-T cell activation: nanofibrillar cellulose gels as alternative to preserve T cell function in 3D cell cultures

Revilla,

Cutilli,

Rockx-Brouwer

et al. 2024

Preprint

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Background: Hydrogel-based 3D culture systems are emerging as a valuable tool for preclinical screening of cell-based immunotherapies against solid and hematological malignancies, such as chimeric antigen receptor T (CAR-T) cells. Hydrogels can influence T cell function in a non-desired manner due to their mechanical properties and chemical composition, potentially skewing results in preclinical testing of novel immunotherapeutic compounds. Methods: In this study, we assess CD4+ T and CAR-T cell activation and proliferation in chemically-undefined matrices (Matrigel and basement membrane extract, BME) and compare them to a synthetic nanofibrillar cellulose (NFC) hydrogel. Results: Rheometric analyses show that NFC is more rigid than Matrigel and BME. Murine CD4+ T cells acquire a regulatory T cell (Treg) phenotype in Matrigel and BME, while this is not observed in NFC. Proliferation and activation of human T cells are higher in NFC than in Matrigel or BME. Similarly, we show that CAR-T cell activation and proliferation is significantly impaired in Matrigel and BME, in contrast to NFC. Conclusions: Our findings highlight the impact of hydrogel choice on (CAR-)T cell behavior, with direct implications for preclinical immunotherapy testing. In contrast to Matrigel and BME, NFC offers a chemically-defined 3D environment where T cell function is preserved.

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Utilizing 3D Models to Unravel the Dynamics of Myeloma Plasma Cells’ Escape from the Bone Marrow Microenvironment

Cited by 2 publications

References 96 publications

In vitro models of the crosstalk between multiple myeloma and stromal cells recapitulate the mild NF-κB activation observed in vivo

In vitro models of the crosstalk between multiple myeloma and stromal cells recapitulate the mild NF-κB activation observed in vivo

Basement membrane hydrogels dampen CAR-T cell activation: nanofibrillar cellulose gels as alternative to preserve T cell function in 3D cell cultures

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