Transcriptional Remodeling of the Stromal and Endothelial Microenvironment in MGUS to Multiple Myeloma Progression

Abstract

Despite therapeutic advancements, Multiple Myeloma (MM) remains an incurable disease. To characterize the role that deregulation of the Bone Marrow (BM) microenvironment may have in the transition from healthy to Monoclonal Gammopathy of Undetermined Significance (MGUS), and from MGUS to MM, we performed single-cell RNA sequencing (scRNA-seq) of mesenchymal stromal cells (MSC) and endothelial cells (EC) from two mouse models, BIcgamma and MIcgamma, that recapitulate the principal clinical, genetic, and immunological characteristics of MGUS and MM patients. Our results identify distinct transcriptional dynamics between MSC and EC. While EC acquires a stress state during MGUS, a proliferating and angiogenic profile characterizes MM. On the other hand, MSC compromised their differentiation potential, exhibiting a more inflammatory profile that initiates from the MGUS stage. Interestingly, we identified interferon (IFN)-related myeloma signature in malignant EC of the BIcgamma model, which is also expressed in MSC but not observed in the most aggressive MIcgamma model and can be identified in a subgroup of MM patients. The analysis of the MSC and EC interactions with PC revealed stage-specific interactions of relevance for angiogenesis, immunomodulation, and MM extravasation. Finally, the translational relevance of our results in humans was confirmed on MSC from newly diagnosed patients at different stages of the disease. In summary, these results indicate a remodeling of the non-hematopoietic BM microenvironment in myeloma progression, providing potential targets at the tumor-niche interface that may hold clinical significance and complement existing immunotherapies.