Molecular dissection of signaling pathways exerting bone anabolic and anti-tumor effects of physical stimuli in myeloma bone disease

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Multiple myeloma (MM) is a malignant plasma cell disorder, in which tumor cells induce osteolytic bone disease. While anabolic treatment of bone disease in malignancies is still a matter of discussion, a non-pharmacological approach to prevent or rescue osteopenia is the use of well-controlled physical stimuli. In preclinical MM studies we have shown that physical stimuli in the form of mechanical loading have promising bone-sparing outcomes and even mitigate tumor cell growth and dissemination. Transcriptome profiling of cortical osteocytes revealed substantial alterations of gene expression caused by tumor cells in a set of extracellular matrix-related genes which were rescued or stimulated by mechanical loading. Cell adhesion is an important component of mechanical loading in tissue and the tightness of adhesion mechanisms is enforced by loading. While analyzing subpopulations of MM cells in vitro that adhered with different forces to skeletal precursors we found a characteristic set of differentially expressed genes in tightly adhering MM cells. We identified a partial overlap between the in vivo and in vitro gene sets representing a convincing interactive gene network in which candidates belong to three clusters of (1) skeletal development, (2) lipid transport and (3) extracellular matrix organization. In addition, we found that low expression of lead candidates from this network like the low-density lipoprotein receptor-related protein 1 (LRP1) is associated with worse MM patient survival using large cohorts of clinically derived RNAseq data. In this project we will molecularly dissect the networks behind adhesion / mechanotransduction and tumor homing and spread, searching for effective types of mechanical loading and innovative druggable targets that address the bone anabolic and anti-tumor effects. We hypothesize that LRP1 is a lead candidate for a hub orchestrating mechanoresponsive bone remodeling and mediating rescue effects of physical stimulation in MM and bone cells. LRP1 expression is diminished in bone in the presence of MM and its bone specific knockout was shown in the past to severely disrupt bone remodeling. Similarly, Serpin H1, a chaperone essential for collagen folding and integrity, mediates tight MM cell adhesion and controls extracellular matrix production in bone cells. It will be proven both in vitro by interaction experiments between skeletal precursors, osteocyte cell lines and MM cells and in vivo in respective mouse models where adhesion / loading conditions are modulated using whole-body low-magnitude high frequency vibration, genetic engineering of MM cells and pharmacological modulation of LRP1 and Serpin H1 signaling. This will allow for identifying targets in models of mechanical loading that can be addressed to reconstitute healthy bone tissue and at the same time impart anti-tumor effects in the microenvironment.