Ex vivo propagation in a novel 3D high-throughput co-culture system for multiple myeloma

Purpose Multiple myeloma (MM) remains an incurable hematologic malignancy which ultimately develops drug resistance and evades treatment. Despite substantial therapeutic advances over the past years, the clinical failure rate of preclinically promising anti-MM drugs remains substantial. More realist...

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Bibliographic Details
Published in:Journal of cancer research and clinical oncology 2022-05, Vol.148 (5), p.1045-1055
Main Authors: Waldschmidt, Johannes M., Fruttiger, Stefan J., Wider, Dagmar, Jung, Johannes, Thomsen, Andreas R., Hartmann, Tanja N., Duyster, Justus, Hug, Martin J., Azab, Kareem A., Jung, Manfred, Wäsch, Ralph, Engelhardt, Monika
Format: Article
Language:English
Subjects:
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Auranofin - pharmacology
Bortezomib
Bortezomib - pharmacology
Bortezomib - therapeutic use
Cancer Research
Cell culture
Cell growth
Cell Line, Tumor
Cell proliferation
Coculture Techniques
Cytotoxicity
Drug resistance
Hematology
Humans
Internal Medicine
Malignancy
Medicine
Medicine & Public Health
Multiple myeloma
Multiple Myeloma - pathology
Oncology
Original Article – Cancer Research
Original – Cancer Research
Propagation
Targeted cancer therapy
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Summary:Purpose Multiple myeloma (MM) remains an incurable hematologic malignancy which ultimately develops drug resistance and evades treatment. Despite substantial therapeutic advances over the past years, the clinical failure rate of preclinically promising anti-MM drugs remains substantial. More realistic in vitro models are thus required to better predict clinical efficacy of a preclinically active compound. Methods Here, we report on the establishment of a conical agarose 3D co-culture platform for the preclinical propagation of primary MM cells ex vivo. Cell growth was compared to yet established 2D and liquid overlay systems. MM cell lines (MMCL: RPMI-8226, U266, OPM-2) and primary patient specimens were tested. Drug sensitivity was examined by exploring the cytotoxic effect of bortezomib and the deubiquitinase inhibitor auranofin under various conditions. Results In contrast to 2D and liquid overlay, cell proliferation in the 3D array followed a sigmoidal curve characterized by an initial growth delay but more durable proliferation of MMCL over 12 days of culture. Primary MM specimens did not expand in ex vivo monoculture, but required co-culture support by a human stromal cell line (HS-5, MSP-1). HS-5 induced a > fivefold increase in cluster volume and maintained long-term viability of primary MM cells for up to 21 days. Bortezomib and auranofin induced less cytotoxicity under 3D vs. 2D condition and in co- vs. monoculture, respectively. Conclusions This study introduces a novel model that is capable of long-term propagation and drug testing of primary MM specimens ex vivo overcoming some of the pitfalls of currently available in vitro models.
ISSN:0171-5216
1432-1335
DOI:10.1007/s00432-021-03854-6