Abstract
Physical interaction of skeletal precursors with multiple myeloma cells has been shown to suppress their osteogenic potential while favoring their tumor-promoting features. Although several transcriptome analyses of myeloma patient-derived mesenchymal stem cells have displayed differences compared to their healthy counterparts, these analyses insufficiently reflect the signatures mediated by tumor cell contact, vary due to different methodologies, and lack results in lineage-committed precursors.To determine tumor cell contact-mediated changes on skeletal precursors, we performed transcriptome analyses of mesenchymal stem cells and osteogenic precursor cells cultured in contact with the myeloma cell line INA-6. Comparative analyses confirmed dysregulation of genes which code for known disease-relevant factors and additionally revealed upregulation of genes that are associated with plasma cell homing, adhesion, osteoclastogenesis, and angiogenesis. Osteoclast-derived coupling factors, a dysregulated adipogenic potential, and an imbalance in favor of anti-anabolic factors may play a role in the hampered osteoblast differentiation potential of mesenchymal stem cells. Angiopoietin-Like 4 (ANGPTL4) was selected from a list of differentially expressed genes as a myeloma cell contact-dependent target in skeletal precursor cells which warranted further functional analyses. Adhesion assays with full-length ANGPTL4-coated plates revealed a potential role of this protein in INA-6 cell attachment.This study expands knowledge of the myeloma cell contact-induced signature in the stromal compartment of myelomatous bones and thus offers potential targets that may allow detection and treatment of myeloma bone disease at an early stage.
Highlights
Since myeloma cells are known to hamper osteogenic lineage commitment of mesenchymal stem cells (MSC) [9], we first investigated the effect of INA-6 cell contact on the osteogenic commitment of MSC by staining active alkaline phosphatase (ALP) in 2D coculture that had been incubated with osteogenic differentiation medium for two weeks (Fig. 1A)
Our data show for the first time, to the best of our knowledge, microarray analysis of osteogenically pre-differentiated MSC (OPC) that had been in contact with MM cells
These findings support the importance of the crosstalk of MM cells with skeletal precursor cells for myeloma bone disease development
Summary
Multiple myeloma (MM) is a plasma cell neoplasia that is still largely incurable, the median 10-year survival has increased to 40% in patients b 50 years of age due to the development of new drugs and bone marrow transplantation strategies during the last two decades [1]. We performed a thorough transcriptome analysis of both MSC and OPC after direct contact with MM cells These results show that OPC are capable of supporting MM progression, albeit to a lesser extent than MSC, which seem to have a greater tumor-promoting potential according to the genetic signature. We identified Angiopoietin-Like 4 (ANGPTL4) as a novel interaction-specific target of skeletal precursors that mediates myeloma cell attachment. These data support the potent role of stroma in pathophysiological mechanisms favoring MM bone disease and provide insights into molecular mechanisms and signaling pathways that are associated with the development of bone metastases and niche hijacking in general
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