Modeling Myeloma Dissemination In Vitro with hMSC-interacting Subpopulations of INA-6 Cells and Their Aggregation/Detachment Dynamics

Author:

Kuric Martin1ORCID,Beck Susanne2ORCID,Schneider Doris1ORCID,Rindt Wyonna3ORCID,Evers Marietheres4ORCID,Meißner-Weigl Jutta1ORCID,Zeck Sabine1ORCID,Krug Melanie1ORCID,Herrmann Marietta5ORCID,Hartmann Tanja Nicole6ORCID,Leich Ellen4ORCID,Rudert Maximilian7ORCID,Docheva Denitsa1ORCID,Seckinger Anja8ORCID,Hose Dirk8ORCID,Jundt Franziska3ORCID,Ebert Regina1ORCID

Affiliation:

1. 1Department of Musculoskeletal Tissue Regeneration, University of Würzburg, Würzburg, Germany.

2. 2University Hospital Heidelberg, Institute of Pathology, Heidelberg, Germany.

3. 3Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.

4. 4University of Würzburg, Institute of Pathology, Comprehensive Cancer Center Mainfranken, Würzburg, Germany.

5. 5University Hospital Würzburg, IZKF Research Group Tissue Regeneration in Musculoskeletal Diseases, Würzburg, Germany.

6. 6Department of Internal Medicine I, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.

7. 7Orthopedic Department, Clinic König-Ludwig-Haus, University of Würzburg, Würzburg, Germany.

8. 8Department of Hematology and Immunology, Vrije Universiteit Brussel, Jette, Belgium.

Abstract

Abstract Multiple myeloma involves early dissemination of malignant plasma cells across the bone marrow; however, the initial steps of dissemination remain unclear. Human bone marrow–derived mesenchymal stromal cells (hMSC) stimulate myeloma cell expansion (e.g., IL6) and simultaneously retain myeloma cells via chemokines (e.g., CXCL12) and adhesion factors. Hence, we hypothesized that the imbalance between cell division and retention drives dissemination. We present an in vitro model using primary hMSCs cocultured with INA-6 myeloma cells. Time-lapse microscopy revealed proliferation and attachment/detachment dynamics. Separation techniques (V-well adhesion assay and well plate sandwich centrifugation) were established to isolate MSC-interacting myeloma subpopulations that were characterized by RNA sequencing, cell viability, and apoptosis. Results were correlated with gene expression data (n = 837) and survival of patients with myeloma (n = 536). On dispersed hMSCs, INA-6 saturate hMSC surface before proliferating into large homotypic aggregates, from which single cells detached completely. On confluent hMSCs, aggregates were replaced by strong heterotypic hMSC–INA-6 interactions, which modulated apoptosis time dependently. Only INA-6 daughter cells (nMA-INA6) detached from hMSCs by cell division but sustained adherence to hMSC-adhering mother cells (MA-INA6). Isolated nMA-INA6 indicated hMSC autonomy through superior viability after IL6 withdrawal and upregulation of proliferation-related genes. MA-INA6 upregulated adhesion and retention factors (CXCL12), that, intriguingly, were highly expressed in myeloma samples from patients with longer overall and progression-free survival, but their expression decreased in relapsed myeloma samples. Altogether, in vitro dissemination of INA-6 is driven by detaching daughter cells after a cycle of hMSC-(re)attachment and proliferation, involving adhesion factors that represent a bone marrow–retentive phenotype with potential clinical relevance. Significance: Novel methods describe in vitro dissemination of myeloma cells as detachment of daughter cells after cell division. Myeloma adhesion genes were identified that counteract in vitro detachment with potential clinical relevance.

Funder

Deutsche Forschungsgemeinschaft

Deutsche Krebshilfe

Wilhelm Sander-Stiftung

Interdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum Würzburg

Publisher

American Association for Cancer Research (AACR)

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