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Saxena, Madhurima

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Saxena

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Madhurima

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Saxena, Madhurima
Author's Publications: search.filters.isAuthorOfPublication.96d5f361-0828-473e-82dc-70e32072c831

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    Single-Cell Transcript Profiles Reveal Multilineage Priming in Early Progenitors Derived from Lgr5 + Intestinal Stem Cells
    (Elsevier BV, 2016-08) Kim, Tae-Hee; Saadatpour, Assieh; Guo, Guoji; Saxena, Madhurima; Cavazza, Alessia; Desai, Niyati; Jadhav, Unmesh; Jiang, Lan; Rivera, Miguel; Orkin, Stuart; Yuan, Guo-Cheng; Shivdasani, Ramesh
    Lgr5+ intestinal stem cells (ISC) drive epithelial self-renewal, and their immediate progeny – intestinal bipotential progenitors – produce absorptive and secretory lineages via lateral inhibition. To define features of early transit from the ISC compartment, we used a microfluidics approach to measure selected stem- and lineage-specific transcripts in single Lgr5+ cells. We identified two distinct cell populations, one that expresses known ISC markers and a second, abundant population that simultaneously expresses markers of stem and mature absorptive and secretory cells. Single-molecule mRNA in situ hybridization and immunofluorescence verified expression of lineage-restricted genes in a subset of Lgr5+ cells in vivo. Transcriptional network analysis revealed that one group of Lgr5+ cells arises from the other and displays characteristics expected of bipotential progenitors, including activation of Notch ligand and cell-cycle inhibitor genes. These findings define the earliest steps in ISC differentiation and reveal multilineage gene priming as a fundamental property of the process.
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    The Arf-like GTPase Arl8b is essential for three-dimensional invasive growth of prostate cancer in vitro and xenograft formation and growth in vivo
    (Impact Journals LLC, 2016) Dykes, Samantha S.; Gray, Alana L.; Coleman, David T.; Saxena, Madhurima; Stephens, Charles A.; Carroll, Jennifer L.; Pruitt, Kevin; Cardelli, James A.
    Cancer is a multistep process that requires cells to respond appropriately to the tumor microenvironment, both in early proliferative stages and in later invasive disease. Arl8b is a lysosome localized Arf-like GTPase that controls the spatial distribution of lysosomes via recruitment of kinesin motors. Common features of the tumor microenvironment such as acidic extracellular pH and various growthfactors stimulate lysosome trafficking to the cell periphery (anterograde), which is critical for tumor invasion by facilitating the release of lysosomal proteases to promote matrix remodeling. Herein we report for the first time that Arl8b regulates anterograde lysosome trafficking in response to hepatocyte growth factor, epidermal growth factor, and acidic extracellular pH. Depletion of Arl8b results in juxtanuclear lysosome aggregation, and this effect corresponds with both diminished invasive growth and proteolytic extracellular matrix degradation in a three-dimensional model of prostate cancer. Strikingly, we found that depletion of Arl8b abolishes the ability of prostate cancer cells to establish subcutaneous xenografts in mice. We present evidence that Arl8b facilitates lipid hydrolysis to maintain efficient metabolism for a proliferative capacity in low nutrient environments, suggesting a likely explanation for the complete inability of Arl8b-depleted tumor cells to grow in vivo. In conclusion, we have identified two mechanisms by which Arl8b regulates cancer progression: 1) through lysosome positioning and protease release leading to an invasive phenotype and 2) through control of lipid metabolism to support cellular proliferation. These novel roles highlight that Arl8b is a potential target for the development of novel anti-cancer therapeutics.