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

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.

Autophagy and the Bone Marrow Microenvironment: A Review of Protective Factors in the Development and Maintenance of Multiple Myeloma

“…When APRIL binds to BCMA, NFkB-mediated XBP-1 activation of UPR and autophagy pathways in PCs promote signaling pathways mediating cell growth and survival ( 59 , 60 ). It was also shown in recent 3D models that MM and MGUS BM core samples exposed to IL-6 had increased CD138+ PCs after five days, indicating that in both stages of disease IL-6 provides significant pro-survival activity ( 43 ). This, in addition to the previous pathways for disease progression, demonstrates how important IL-6 is to MM pathogenesis and maintenance.…”

“…A recent study compared the BM of MGUS and MM patients. While the PCs in both samples were incredibly variable with many shared characteristics, only the MM patient PCs showed significantly increased autophagy ( 43 ). This finding highlights the potential importance of autophagy for the progression of MGUS to MM.…”

“…These pathways could help explain recent findings that MM patients have increased fibronectin in the BM stroma compared to MGUS patients. This increase in fibronectin was accompanied by an increase in CD138+ cells, which is a marker for PCs ( 43 ). These pathways could help explain both findings, suggesting that increased fibronectin is integral to the development of MM and the increase in PCs associated with the disease, though further research would be needed to confirm these observations.…”

“…Continued research in the development and use of caspase 10 inhibitors, such as Z-AEVD-FMK, may be beneficial in conjunction with bortezomib to push resistant MM cells towards cell death. More effective treatments may also embrace implementing 3D models based on the patient BM microenvironment to better simulate the patient’s disease progression and test potential treatments ( 43 , 82 ). These 3D models can also be used to closely monitor progression of the disease for the purpose of rapid modification of treatment ( 43 ).…”

“…More effective treatments may also embrace implementing 3D models based on the patient BM microenvironment to better simulate the patient’s disease progression and test potential treatments ( 43 , 82 ). These 3D models can also be used to closely monitor progression of the disease for the purpose of rapid modification of treatment ( 43 ).…”