Abstract
Multiple myeloma (MM) is a malignancy of terminally-differentiated plasma cells that develops mainly inside the bone marrow (BM) microenvironment. It is well known that autocrine and paracrine signals are responsible for the progression of this disease but the precise mechanism and contributions from single cell remain largely unknown. Mesenchymal stem cells (MSC) are an important cellular component of the BM: they support MM growth by increasing its survival and chemo-resistance, but little is known about the paracrine signaling pathways. Three-dimensional (3D) models of MM-MSC paracrine interactions are much more biologically-relevant than simple 2D models and are considered essential for detailed studies of MM pathogenesis.Herein we present a novel 3D co-culture model designed to mimic the paracrine interaction between MSC and MM cells. MSC were embedded within a previously characterized thermoresponsive block copolymer worm gel that can induce stasis in human pluripotent stem cells (hPSC) and then co-cultured with MM cells. Transcriptional phenotyping of co-cultured cells indicated the dysregulation of genes that code for known disease-relevant factors, and also revealed IL-6 and IL-10 as upstream regulators. Importantly, we have identified a synergistic paracrine signaling pathway between IL-6 and IL-10 that plays a critical role in sustaining MM cell proliferation.Our findings indicate that this 3D co-culture system is a useful model to investigate the paracrine interaction between MM cells and the BM microenvironment in vitro. This approach has revealed a new mechanism that promotes the proliferation of MM cells and suggested a new therapeutic target.
Highlights
Multiple myeloma (MM) is a B-cell neoplasia that develops within the bone marrow (BM) microenvironment that sustains the induction, selection and expansion of cancer cells [1,2,3]
Our findings indicate that this 3D co-culture system is a useful model to investigate the paracrine interaction between MM cells and the BM microenvironment in vitro
We performed Upstream Regulator Analysis (URA) on co-cultured MM cells to identify potential upstream regulators induced by the paracrine interaction with Mesenchymal stem cells (MSC) and able to modulate different functions in MM. Using this approach for the most significant upstream regulators (Bonferroni corrected p-value < 0.05), we found some of the cytokines reported to be implicated with MM progression (Fig. 3A) including IL-6 and IL-10, which were reported to be involved in MM cell proliferation [39,40]
Summary
Multiple myeloma (MM) is a B-cell neoplasia that develops within the bone marrow (BM) microenvironment that sustains the induction, selection and expansion of cancer cells [1,2,3]. The abnormal growth of malignant plasma cells is strongly dependent on autocrine and paracrine loops involving the surrounding microenvironment that supports MM cell proliferation, survival, migration and chemo-resistance [4,5]. Mesenchymal stem cells (MSC) are a key cellular component of the BM; they are capable of self-renewal and differentiation and are known to play multiple roles in tumor progression [8,9]. MSC support MM cell growth, survival and drug resistance through paracrine circuits [10,11], but little is known about the respective mechanisms
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