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Structural and Ultrastructural Analysis of the Multiple Myeloma Cell Niche and a Patient-Specific Model of Plasma Cell Dysfunction

Published online by Cambridge University Press:  09 December 2021

Katrina A. Harmon ,
Sara Roman ,
Harrison D. Lancaster ,
Saeeda Chowhury ,
Elizabeth Cull ,
Richard L. Goodwin Open the ORCID record for Richard L. Goodwin [Opens in a new window] ,
Sergio Arce Open the ORCID record for Sergio Arce [Opens in a new window]  and
Suzanne Fanning
Katrina A. Harmon
Affiliation:
Organogenesis, Birmingham, AL35216, USA
Sara Roman
Affiliation:
Altasciences, Greenville, SC29601, USA
Harrison D. Lancaster
Affiliation:
School of Medicine Greenville, University of South Carolina, Greenville, SC 29605, USA
Saeeda Chowhury
Affiliation:
School of Medicine Greenville, University of South Carolina, Greenville, SC 29605, USA Department of Internal Medicine, Prisma Health System Upstate, Greenville, SC29605, USA Prisma Health Cancer Institute, Greenville, SC29605, USA
Elizabeth Cull
Affiliation:
School of Medicine Greenville, University of South Carolina, Greenville, SC 29605, USA Department of Internal Medicine, Prisma Health System Upstate, Greenville, SC29605, USA Prisma Health Cancer Institute, Greenville, SC29605, USA
Richard L. Goodwin*
Affiliation:
School of Medicine Greenville, University of South Carolina, Greenville, SC 29605, USA
Sergio Arce
Affiliation:
School of Medicine Greenville, University of South Carolina, Greenville, SC 29605, USA Prisma Health Cancer Institute, Greenville, SC29605, USA
Suzanne Fanning
Affiliation:
School of Medicine Greenville, University of South Carolina, Greenville, SC 29605, USA Department of Internal Medicine, Prisma Health System Upstate, Greenville, SC29605, USA Prisma Health Cancer Institute, Greenville, SC29605, USA
*
*Corresponding author: Richard L. Goodwin, E-mail: [email protected]
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Abstract

Multiple myeloma (MM) is a deadly, incurable malignancy in which antibody-secreting plasma cells (PCs) become neoplastic. Previous studies have shown that the PC niche plays a role cancer progression. Bone marrow (BM) cores from MM and a premalignant condition known as monoclonal gammopathy of unknown significance (MGUS) patients were analyzed with confocal and transmission electron microscopy. The BM aspirates from these patients were used to generate 3D PC cultures. These in vitro cultures were then assayed for the molecular, cellular, and ultrastructural hallmarks of dysfunctional PC at days 1 and 5. In vivo, evidence of PC endoplasmic reticulum stress was found in both MM and MGUS BM; however, evidence of PC autophagy was found only in MM BM. Analysis of in vitro cultures found that MM PC can survive and maintain a differentiated phenotype over an unprecedented 5 days, had higher levels of paraprotein production when compared to MGUS-derived cultures, and showed evidence of PC autophagy as well. Increased fibronectin deposition around PC associated with disease severity and autophagy dysregulation was also observed. 3D cultures constructed from BM aspirates from MGUS and MM patients allow for long-term culture of functional PC while maintaining their distinct morphological phenotypes.

Keywords

3D cultureautophagyendoplasmic reticulum stressfibronectinmyelomaplasma cellssurvival niche
Type
Biological Applications
Information
Microscopy and Microanalysis , Volume 28 , Issue 1 , February 2022 , pp. 254 - 264
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Copyright
Copyright © The Author(s), 2021. Published by Cambridge University Press on behalf of the Microscopy Society of America

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Footnotes

a

These two authors are co-senior authors.

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