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P&F Grant Awards

Year 5


Grant # 8

The Role of Stromal Senescence in MGUS and Multiple Myeloma

PI: Michelle Hurchla, Ph.D.,

 

Specific Aims

Multiple Myeloma (MM) results from the growth of malignant antibody-secreting plasma cell clones within the bone marrow (BM) and is associated with debilitating osteolytic bone lesions. Monoclonal gammopathy of undetermined significance (MGUS), the pre-neoplastic condition preceding all myelomas, is a common disease of aging, occurring in 3.2% and 5.3% of individuals >50 or >70 years old1, respectively. Importantly, MGUS is associated with osteoporosis and increased fracture rate2. The biological basis for the transition from relatively benign MGUS to invariably fatal MM remains unknown. Interestingly, nearly all of the tumoral genetic changes identified in MM are also found in MGUS, suggesting that another factor such as the microenvironment plays a role in disease progression. Senescence, the cellular aging process in which cells lose the ability to divide, is recognized to be a driver of aging associated diseases including cancer, arthritis and arthrosclerosis. The Stewart lab and others have found that senescent fibroblasts produce numerous growth factors and cytokines referred to as the senescent associated secretory phenotype (SASP) that can promote tumor development. Notably, IL-6 is one of the most abundant SASP factors and is also a key factor in myeloma growth. We hypothesize that activation of the senescence-associated secretory program in patient bone marrow stromal cells is a critical switch that causes relatively innocuous MGUS to progress to bone-destructive MM. Aim 1: Do senescent BMSC support myeloma cell growth and tumor associated bone loss? Aim 2: Can engineered senescence in bone enhance myeloma growth and associated bone loss? Bone marrow stromal cells (BMSC) are a phenotypically heterogeneous population that includes mesenchymal stem cells (MSC), the progenitors of osteoblasts (OB). BMSC regulate both osteoclasts (OC) (production of MCSF and RANKL) and support myeloma growth (adhesion and growth factor production). Dr. Hurchla, recently promoted to Instructor, is developing her independent research program to study microenvironmental control of myeloma bone disease. The Weilbaecher Lab is recognized as an expert in osteolysis induced by metastatic breast cancer and melanoma. The Stewart Lab is a leader in the study of how cellular aging supports tumorigenesis. They have developed novel methods to induce and identify SASP and have developed a mouse in which stromal senescence in bone can be established in young mice (FAAST mice). Using a genetic approach, the Tomasson Lab has generated a short list of candidate genes, including some with roles in bone biology responsible for MGUS/MM development in the genetically uncharacterized KaLwRij mouse strain. Drs. Michael Tomasson and Ravi Vij have established a MM/MGUS tumor bank and in collaboration with the Weilbaecher Lab have produced primary MM patient BMSC that will be used in this proposal. We have established this collaborative group to utilize the unique expertise and resources of each member to interrogate the complex interactions between stromal senescence, myelomagenesis and osteolytic disease. We ask for pilot money from the Musculoskeletal Program to obtain critical preliminary data for: 1) Dr. Hurchla’s K22 application in October 2013; 2) a bone/stroma/senescence project in the Myeloma program U01 grant application (PI Tomasson, Project PIs Hurchla, Stewart, Weilbaecher) due September 2013.