Bone marrow niche regulation of disseminated tumor cell dormancy, reactivation, and metastasis.

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PROJECT SUMMARY / ABSTRACT Metastatic relapse may occur in patients with ER+ breast cancer decades after original diagnosis. Most breast cancer related deaths are caused by metastasis and thus identifying at-risk patients and developing therapies to prevent reactivation are a crucial challenge. These efforts have been impeded by a lack of understanding of cancer cell dormancy in the bone marrow, believed to be the cellular source of metastatic relapse. It is not well understood how tumor cells interact with the bone marrow microenvironment and how these interactions regulate tumor cell dormancy and escape. My proposed research seeks to develop a mouse model of dormancy and investigate the spatial organization of the bone marrow niche in patient samples in the mentored K99 phase and develop a biomaterial model of dormancy in the independent R00 phase. I hypothesize (i) cancer stem cells are a subset of disseminated tumor cells responsible for metastatic relapse and (ii) the bone marrow niche, including the healthy stem cell niche, facilitates dormancy and reactivation of these cells. In Aim 1, I will develop a novel mouse model of hormone responsive breast cancer dormancy in bone marrow and evaluate the presence, phenotype, and microenvironmental regulation of disseminated tumor cells using optical tissue clearing/3D imaging of whole bone. In Aim 2, I will investigate the hypothesis that tumor cell interactions with the bone marrow niche control tumor cell phenotype via high dimensional spatial analysis of bone marrow biopsies from patients with breast cancer including imaging mass cytometry (IMC) and spatial single cell RNA sequencing (scRNAseq). In Aim 3, I will develop a biomaterial model of the dormant bone marrow niche via creating mechanical mimics of the three distinct compartments of bone marrow and evaluate the role of mechanosensing in induction and maintenance of dormancy. In the K99 phase of the award, Prof Max Wicha will serve as my main mentor. Dr. Wicha is a pioneer in the cancer stem cell field and is an expert in breast cancer biology and metastasis. I will work with and consult my collaborators and mentoring team, including Prof Fei Wen (imaging mass cytometry), Evan Keller (single cell spatial analysis program), Dr. Dafydd Thomas (pathology core), Prof Gary Luker (microscopy), Prof Monika Burness (breast cancer clinical oncology) and Prof Sofia Merjaver (breast cancer molecular biology). My K99 training will consist of developing a novel mouse model of bone marrow dormancy and learning bioinformatics approaches to analyze spatial contributions to cellular phenotype in IMC and scRNAseq data to propel me toward developing a synthetic dormant bone marrow niche mimic using biomaterials during the independent R00 phase. In sum, the proposed research will address an urgent, unmet need to identify the role of the bone marrow niche in breast cancer dormancy and reactivation, which may provide a path forward for identifying patients at higher risk of metastasis and developing therapies against reactivation.