Michael J. Strong, MD, FRCP(C), FANN, FCAHS - US grants

DESCRIPTION (provided by applicant): Viral infections are associated with several human malignancies, yet the role of viral infections in the central nervous system (CNS) tumors remains unclear. Although human cytomegalovirus (HCMV) has been associated with glioblastoma multiforme (GBM), the mechanisms of pathogenesis remain to be determined. GBM is the most common primary malignancy in the CNS, and unfortunately, it is also one of the most devastating. Novel approaches to studying this disease are paramount for the advancement in treatment options for patients with this dismal disease. Using robust next generation sequencing technology, this project aims to provide insight into HCMV biology related to GBMs. In addition, investigation of the tumor microenvironment for HCMV specific host cellular gene changes will lead to the discovery of pathways in which HCMV dysregulation promotes GBM pathology. The overarching hypothesis for this project is that HCMV contributes to GBM pathogenesis through modulation of the tumor microenvironment.

PROJECT SUMMARY/ABSTRACT Roughly 400,000 people in the U.S. have bone metastases, the vast majority occurring in the spine. Metastases to the spine results in fractures, pain, paralysis, and enormous health care costs. This pathological process is not fully understood. Immune cells are an important constituent of the bone marrow microenvironment and have been shown to play a significant role in tumor growth and progression in soft tissue disease specifically myeloid cells. Additionally, immune cell composition within the bone marrow microenvironment may vary by location, further contributing to immune escape of cancer cells and variable rates of metastases. The role of the immune microenvironment in bone marrow and the differential expression of myeloid cells in different bones has not been extensively investigated. We have preliminarily examined the immune microenvironments in different bone regions and observed differences in the immune cell populations between the spine and the femur. Based on previous research in soft tissue tumor progression and our novel preliminary data, we will further investigate these differences in local bone immune environments to glean knowledge that can be translated into targeted therapies that limit or prevent metastases to the spine. We therefore hypothesize that there is an immunosuppressive signature, driven by changes in the myeloid population, in the vertebral bodies compared to the long bones and that in the setting of cancer, this signature is enhanced. Our approach utilizes high-fidelity, high-throughput technology in the form of time-of-flight mass spectrometry (CyTOF) and single-cell RNA-seq (scRNA-seq) to globally interrogate cell populations in the context of a particularly heterogeneous background to construct insights into the oncogenic signaling pathways linking immune cells to the tumor-promoting phenotype within the bone marrow niche. To test our hypothesis, we propose the following two specific aims: 1) Characterize the differences in the native and premetastatic immune cell landscapes between the vertebrae and long bone. 2) Determine the functional significance of immune population differences between vertebrae and long bones on tumor initiation and permissive growth to spine. The applicant assembled a mentorship committee of high quality and specific specialties available at the University of Michigan. This strong mentorship committee, training environment, and research proposal will provide the necessary resources to successfully complete this proposed project. Results from this proposal will advance our understanding of bone metastases and bone immunology and facilitate the identification of unique highly specific targets that may be used in alternative therapies to improve clinical outcomes for patients with spine metastases. Additionally, this project will foster for the applicant a new skillset that can be used in this emerging field of osteoimmunology and metastatic disease. Ultimately, the applicant will use this award to generate additional data for obtaining extramural funding and advancing his career as a surgeon scientist in the field of spine oncology and osteoimmunology.