Spatial Transcriptomics Reveals a Myeloma Cell Architecture with Dysfunctional T-Cell Distribution, Neutrophil Traps, and Inflammatory Signaling

Abstract

ABSTRACTUnderstanding the spatial organization of the bone marrow (BM) microenvironment at single-cell resolution constitutes a challenge in multiple myeloma (MM). Using formalin-fixed paraffin-embedded (FFPE) samples from the MIcγ1 mouse model of MM and aged-matched healthy YFPcγ1 mice, we performed spatial transcriptional profiling with Visium Spatial Gene Expression. A custom data-analysis framework that combines spatial with single-cell transcriptomic profiling defined the BM cellular composition and established specific cell relations, visualizing the spatial distribution of transcriptionally heterogeneous MM plasma cells (MM-PC). MM pathogenesis transcriptional programs were spatially delineated within the BM microenvironment. A high-to-low MM-PC density gradient spatially correlated with effector-to-exhausted T cell phenotype abundance. In this context, MM cells in high-density MM-PC areas coexisted with dendritic cells while displaced neutrophils to the tumor border. Increased neutrophil extracellular trap formation, IL-17-driven inflammatory signaling, and osteoclast differentiation were spatially delineated within the BM microenvironment. The spatial identification of different areas of BM and the interaction between malignant cells and their microenvironment were validated in FFPE BM biopsies from MM patients with varying degrees of MM-PC infiltration. In summary, spatial transcriptomics depicts the BM cellular architecture of MM and reveals deregulated mechanisms underlying MM intercellular communication.