Principal Investigator: Prof. David Gomez-Cabrero
Poster Presenter: Aleksandra Kurowska, Azari Bantan
Lab: Living Systems
Multiple myeloma (MM) is a heterogenous malignancy characterized by the abnormal proliferation and infiltration of plasma cells (PCs) into the bone marrow (BM). The development of MM is mediated by distinct genomic aberrations that is preceded by the asymptomatic stages: monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). MM is well known for the abnormal growth of a single clone of malignant PCs leading to the production of non-functional monoclonal immunoglobulin proteins. Several efforts have sought to reveal key characteristics and mechanisms of disease development. However, the epigenetic alterations occurring during the transition of PCs at different stages of MM progression remain poorly understood. Therefore, we aim to address patient heterogeneity and epigenetic landscapes in PCs at distinct stages of MM transition using the state-of-the-art sequencing technologies at both transcriptomic and epigenetic levels. To address intra-tumor and inter-patient heterogeneity we incorporate the analysis of copy number variations, single nucleotide variants, immunoglobulin clonality and mitochondrial DNA mutations. To gain a global understanding of the MM subclones in the BM, we aim to generate a molecular map of all major MM cell populations based on the large public data collection of single-cell RNA sequencing (scRNAseq), which in turn will enhance patient stratification. Further, by integrating scRNAseq and single-cell ATAC sequencing (sATACseq) data of isolated PCs from healthy, MGUS, SMM and MM samples, we want to characterize PCs subtypes that show distinct functional states and reveal transcriptional intra-tumor heterogeneity. Cell proportions can be estimated at the stages of transition to show dynamics in subpopulation abundance resulting in heterogeneous transcriptional regulation of PCs during MM progression. Finally, we utilize human bulk RNAseq and ATACseq, as well as sequenced PCs from MM murine models, for further investigation and validation of our results. Additionally, we use single-cell transcriptomics to dissect the tumor microenvironment interactions within the BM niche. We aim to study cell-to-cell interactions between PCs and endothelial cells (ECs) as well as mesenchymal stem cells (MSCs) in order to learn their roles in MM transitions. Using the single-cell resolution and spatial transcriptomics, we explore the interactions between the PCs and niche cells that display different functional states to uncover refined meta-signatures and mechanisms that regulate disease progression. Collectively, not only we will address patient heterogeneity, but also the combined transcriptional and epigenetic data will allow us to identify core transcriptional factors and tumor-specific enhancer-promoter interactions that impact gene expression and gene regulatory networks, providing a comprehensive insight into the interplay between epigenetic landscapes and gene expression during MM pathogenesis. This will facilitate the development of novel prognostic markers and therapeutic strategies targeting MM-specific dysregulated pathways for personalized medicine.