A ligand-receptor interactome of the bone tumor microenvironment in multiple myeloma bone pain

Multiple myeloma bone pain is a complex multifactorial disease, to which different cell types in the bone marrow microenvironment contribute through ligand-receptor interactions with sensory neurons. We conducted computational analyses of publicly available human and mouse transcriptomic datasets to assess multiple myeloma (MM) microenvironment diversity and identify potential nociceptive interactions. Our results highlight the MM microenvironment heterogeneity and identify cell-type-specific ligand-receptor pairs that potentially stimulate sensory neurons. We tested 7 ligands identified from MM plasma cells and bone marrow stromal cells (insulin-like growth factor 1, macrophage migration inhibitory factor, neuregulin 2, Wnt Family Member 5A, thrombospondin 1, fibroblast growth factor 7, and semaphorin 6A) using Ca 2+ imaging assays in primary cultures of sensory neurons to induce Ca 2+ signaling or affect TRPV1 sensitization. The results showed increased intracellular Ca 2+ levels upon the direct application of thrombospondin 1. To suggest potential targets for future analgesic drug development, we computationally identified MAPK14 and CSNK2A1 as putative regulatory kinases upstream of the identified ligands. Together, our analysis maps potential nociceptive signaling pathways of different MM microenvironment cell types. These pathways extend from upstream regulatory kinases to transcription factors to secreted ligands, which can potentially stimulate sensory neuron receptors in the bone.