Molecular and functional characterization of the normal and malignant plasma cell – bone interface – from single cell mutual interaction analysis to clinical implications in myeloma bone disease and survival

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Multiple Myeloma is a disease of malignant plasma cells spreading and accumulating in the bone marrow with subsequent induction of bone disease and angiogenesis. These features are in common with other malignant diseases. Multiple myeloma is different in two regards: Myeloma cells (MMC) spread to and live in the same “natural environment” as their physiological counterpart, bone marrow plasma cells (BMPC). Further, as shown by us, MMC rely at least partly on normal plasma cell functions for malignant behaviour when inducing angiogenesis and interacting with bone turnover. Malignant like normal plasma cells depend on receiving survival-support by interaction with other cell types in the bone marrow, collectively called “niche”. In vitro, we have shown in myeloma/ mesenchymal stromal cell (MSC)//osteoblast co-cultures that this interaction is prominently exerted by physical interaction and leads to changes in expression and behaviour in both cells types. We hypothesize that this physical interaction creates niches and elicits individual signatures that strengthen adhesion, support tumor cells, and disrupt osteogenesis, clinically leading to bone loss and pathological fractures. Niches may confer dormancy or resistance (minimal residual disease) features to myeloma. We have shown this molecular crosstalk being drugable exemplified by blocking the osteocyte-specific wnt antagonist sclerostin, observing increased osteoblast numbers and bone formation in myeloma bearing mice. We also showed that the contact-induced KISS1R system is a putative target as a theranostic PET tracer.In this application, we will focus on surface molecules featuring the interaction between normal and malignant plasma cells and MSC/osteoblasts. We will use expression analysis including single cell RNA-seq to address population heterogeneity, and functional assessment of interaction by atomic-force microscopy and CRISPR/CAS9 screen with subsequent collaborative in vivo validation in myeloma mouse models. In a second step, our in vitro findings will be related to a large cohort of molecularly characterized malignant plasma cell samples alongside whole-body imaging assessing bone disease, plasma cell infiltration and angiogenesis. We have shown that relation of data at nano-/micro- to large scale clinical data sets can act as a filter for relevance and will allow identification of pre-clinically applicable findings. The first is evidenced by sclerostin being expressed in osteocytes only, in contrast to malignant plasma cells from 630 MM patients; the second by our co-development of the T-cell bispecific antibody EM801/901 against the BMPC/MMC cell-surface molecule BCMA entering clinical trials in Q1/18, building the basis for a separate application for development of a theranostic BCMA-PET-Tracer. We will contribute to a collaborative network for myeloma dissemination, bone disease and angiogenesis related research questions within the µBone-consortium.