Browsing by Subject "CXCL12"

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    Impacts of SDF-1 and radiation dose-rate in an adult zebrafish model of hematopoietic cell transplant
    (2013-05) Glass, Tiffany
    Despite a history of refinements, Hematopoietic Cell Transplant (HCT) remains a potentially difficult treatment that can have high risks for complications and mortality. We used adult zebrafish models of HCT to study two broad biological processes that occur during HCT; homing and early donor-derived hematopoietic reconstitution. In the first case, we validated the adult zebrafish model for the study of the chemokine SDF-1 in HCT, developed a transgenic sdf-1 reporter zebrafish line, and used it to determine sites of high sdf-1 expression in recipient organisms. These sites were discovered both in the hematopoietic tissue as well as in previously un-described structures throughout the skin, and were found to consistently attract donor-derived cells after transplant. Ultimately, this allowed the identification of new putative HSC-niche cells which can be isolated with relative ease. Secondly, we assessed the effects of high conditioning radiation dose-rates on the process of hematopoietic engraftment after transplant. In groups of adult zebrafish given the same total dose of preconditioning radiation, we found that recipients irradiated at a high rate show significantly faster engraftment compared to those irradiated at a lower rate. Insights offered by this work will contribute to future efforts identifying endogenous factors promoting rapid engraftment, as well as to future reassessments of therapeutic opportunities offered by biologically informed refinements of preconditioning radiation strategies.
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    Mechanistic insight into the clonal expansion advantage of quiescent preneoplastic breast cells
    (2018-05) Masoud, Zahra
    Breast cancer, along with most cancers, is preceded by a precancerous state. The majority of cancer research is focused on understanding and targeting cells once they have reached the neoplastic stage. Advancements in early detection have identified the presence of preneoplastic lesions in the breast reporting that cells in these lesions remain phenotypically normal but have pro-growth genetic alterations. These emerging preneoplastic cells carry oncogenic drivers are significantly predisposed to developing tumors, but can stay in a latent state resembling normal quiescent cells in premalignant tissues. Expansion of such preneoplastic populations underlies a key cellular process driving premalignant development and is a hallmark in precancerous lesions and premalignant tissue fields surrounding tumors of epithelial origins such as the breast. Despite the indolent nature, preneoplastic clonal expansion is crucial to propagating and facilitating the accumulation of oncogenic alterations that drive clonal evolution of tumorigenesis and ultimately leads to neoplastic progression. The cellular controls of preneoplastic clonal expansion during premalignant development remain largely unknown. A major barrier to investigating preneoplastic clonal expansion is the lack of experimental models to recapitulate quiescent preneoplastic cells in premalignant tissues. Throughout my PhD research, I have devised a three-dimensional organoid model of quiescent preneoplastic breast cells. Using this model system, I have found that breast cells with aberrant AKT activation have distinct molecular controls that contribute to an altered homeostatic state of quiescence. This altered state underlies the maintenance of growth-arrest under normal conditions and the proliferative advantage in suppressive tissue environments.