The AACR-Millennium Fellowship in Prostate Cancer Research represents a joint effort to encourage and support a postdoctoral or clinical research fellow to conduct prostate cancer research and to establish a successful career path in this field. The research proposed for funding may be basic, translational, clinical or epidemiological in nature and must have direct applicability and relevance to prostate cancer. The Fellowship provides a one-year grant of $55,000 to support the salary and benefits of the Fellow while working on mentored prostate cancer research.
Nicolas Sévère, Ph.D.
Research Fellow, Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA
Study the Role of the Bone Metastatic Microenvironment in Prostate Cancer
"Prostate cancer is the most common cancer in males. It is a heterogeneous disease with multiple genetic aberrations and environmental factors involved in its etiology. Most patients with prostate cancer succumb to their disease because of distant spread to the bone, brain and lung. Approximately two-thirds of patients with advanced prostate cancer develop lesions in bones. Patients with bone metastasis have poor prognosis and have poor quality of life due to severe complication such as bone pain, fractures, hypercalcemia and spinal-cord/nerve compression. It is widely accepted that the tumor microenvironment in the primary tumor but also in the metastatic tumor is crucial for the support of cancer formation and progression. In addition, a dynamic network of growth factors, cytokines, and extracellular matrix proteins provide a permissive ground to ensure the maintenance of cancer cells and protect them from cytotoxic cell death. The bone marrow microenvironment is a complex tissue, composed of several populations of cells including mesenchymal stem cells, osteolineage cells, osteoclasts, adipocytes, endothelial cells, blood cells, hematopoietic stem cells, neurons, immune cells and pericytes. Bone cells results from the differentiation of mesenchymal stem cells into osteoprogenitors followed by osteoblastic differentiation. Previous works in the lab have shown that osteoblastic cells can regulate components of the hematopoietic stem cell niche in vivo. Interestingly, osteoblasts have been shown to interact with prostate cancer (PCa) metastatic cells and promote metastatic growth and might be implicated in resistance to therapy. PCa cells colonizing the bone marrow and compete with hematopoietic stem cells by interacting with osteoblast in order to occupy the bone marrow. These models support the notion that osteolineage cells have a crucial role in support of the pathological niche in the bone marrow. This project seeks to identify if a specific population of osteolineage cells is capable of fostering prostate cancer cells colonization and survival within the bone marrow, and consequently, determine whether selective loss of specific osteolineage cells will change the development of bone metastasis. I will first establish new more aggressive syngenic bone metastatic cell lines from two commonly used transgenic prostate cancer mouse models, the C57BL/6 TRAMP and PBCrePTENfloxP53flox. I will use the InfraRed Fluorescent Molecular Tomography (FMT) imaging to monitor and quantify bone metastatic development in vivo. Then, I will assess colonization, formation and interaction of metastatic prostate cancer cells with different subsets of osteolineage cells using different inducible reporter strains expressing Cre in which a specific population of osteolineage cells can be labeled and traced in vivo (FMT, high-resolution in vivo two photon confocal microscopy) and ex vivo (confocal microscopy and cell-sorted flow cytometry). Furthermore, I will assess how selective loss of specific osteolineage cells changes bone metastatic formation in vivo using the iDTR mice models.
"I am very grateful to receive the Millennium Fellowship in Prostate Cancer Research from the American Association for Cancer Research. This fellowship will give me the opportunity to develop this project and to understand new mechanisms implicated in bone metastasis development in prostate cancer. By using innovative technologies and genetic mice models I will provide crucial information about the role of the bone microenvironment in bone metastases development, and I seek to better understand how bone cells and cancer cells interact in the bone metastatic niche. Characterized the interactions between osteolineage cells and bone invasive prostate cancer cells will give rise to development of new therapeutic strategies to inhibit these specific interactions within the bone marrow and reduce bone metastasis invasion in patient with prostate cancer."
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