サンペトラ，　オルテア (サンペトラ，　オルテア)

Sampetrean, Oltea

写真a

所属（所属キャンパス）

医学部 微生物学・免疫学教室 （信濃町）

職名

助教（有期）

外部リンク
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研究分野 【 表示 ／ 非表示 】

  • ライフサイエンス / 細胞生物学

  • ライフサイエンス / 脳神経外科学

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研究キーワード 【 表示 ／ 非表示 】

  • 悪性グリオーマ

  • 癌

  • 脳腫瘍

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研究テーマ 【 表示 ／ 非表示 】

  • 悪性脳腫瘍幹細胞の特性の解明, 

    2009年04月
    -
    継続中

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  • Elevated cellular PpIX potentiates sonodynamic therapy in a mouse glioma stem cell-bearing glioma model by downregulating the Akt/NF-κB/MDR1 pathway

    Shono K., Mizobuchi Y., Yamaguchi I., Nakajima K., Fujiwara Y., Fujihara T., Kitazato K., Matsuzaki K., Uto Y., Sampetrean O., Saya H., Takagi Y.

    Scientific Reports （Scientific Reports)  11 （ 1 ）  2021年12月

    　概要を見る

    Glioblastoma (GBM) has high mortality rates because of extreme therapeutic resistance. During surgical resection for GBM, 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) fluorescence is conventionally applied to distinguish GBM. However, surgical intervention is insufficient for high invasive GBM. Sonodynamic therapy (SDT) combined with low-intensity ultrasonication (US) and PpIX, as a sonosensitizer, is an emerging and promising approach, although its efficacy is limited. Based on our previous study that down-regulation of multidrug resistant protein (MDR1) in GBM augmented the anti-tumor effects of chemotherapy, we hypothesized that elevation of cellular PpIX levels by down-regulation of MDR1 enhances anti-tumor effects by SDT. In high invasive progeny cells from mouse glioma stem cells (GSCs) and a GSC-bearing mouse glioma model, we assessed the anti-tumor effects of SDT with a COX-2 inhibitor, celecoxib. Down-regulation of MDR1 by celecoxib increased cellular PpIX levels, as well as valspodar, an MDR1 inhibitor, and augmented anti-tumor effects of SDT. MDR1 down-regulation via the Akt/NF-κB pathway by celecoxib was confirmed, using an NF-κB inhibitor, CAPÉ. Thus, elevation of cellar PpIX by down-regulation of MDR1 via the Akt/NF-κB pathway may be crucial to potentiate the efficacy of SDT in a site-directed manner and provide a promising new therapeutic strategy for GBM.

  • MEK inhibition preferentially suppresses anchorage-independent growth in osteosarcoma cells and decreases tumors in vivo

    Shimizu T., Kimura K., Sugihara E., Yamaguchi-Iwai S., Nobusue H., Sampetrean O., Otsuki Y., Fukuchi Y., Saitoh K., Kato K., Soga T., Muto A., Saya H.

    Journal of Orthopaedic Research （Journal of Orthopaedic Research)  39 （ 12 ） 2732 - 2743 2021年12月

    ISSN  07360266

    　概要を見る

    Osteosarcoma is the most common high-grade malignancy of bone, and novel therapeutic options are urgently required. Previously, we developed mouse osteosarcoma AXT cells that can proliferate both under adherent and nonadherent conditions. Based on metabolite levels, nonadherent conditions were more similar to the in vivo environment than adherent conditions. A drug screen identified MEK inhibitors, including trametinib, that preferentially decreased the viability of nonadherent AXT cells. Trametinib inhibited the cell cycle and induced apoptosis in AXT cells, and both effects were stronger under nonadherent conditions. Trametinib also potently decreased viability in U2OS cells, but its effects were less prominent in MG63 or Saos2 cells. By contrast, MG63 and Saos2 cells were more sensitive to PI3K inhibition than AXT or U2OS cells. Notably, the combination of MAPK/ERK kinase (MEK) and PI3K inhibition synergistically decreased viability in U2OS and AXT cells, but this effect was less pronounced in MG63 or Saos2 cells. Therefore, signal dependence for cell survival and crosstalk between MEK–ERK and PI3K–AKT pathways in osteosarcoma are cell context-dependent. The activation status of other kinases including CREB varied in a cell context-dependent manner, which might determine the response to MEK inhibition. A single dose of trametinib was sufficient to decrease the size of the primary tumor and circulating tumor cells in vivo. Moreover, combined administration of trametinib and rapamycin or conventional anticancer drugs further increased antitumor activity. Thus, given optimal biomarkers for predicting its effects, trametinib holds therapeutic potential for the treatment of osteosarcoma.

  • Lactate reprograms energy and lipid metabolism in glucose-deprived oxidative glioma stem cells

    Minami N., Tanaka K., Sasayama T., Kohmura E., Saya H., Sampetrean O.

    Metabolites （Metabolites)  11 （ 5 ）  2021年05月

    　概要を見る

    Fast-growing tumors satisfy their bioenergetic needs by supplementing glucose with alternative carbon sources. Cancer stem cells are the most versatile and robust cells within malignant tumors. They avoid potentially lethal metabolic and other types of stress through flexible reprogramming of relevant pathways, but it has remained unclear whether alternative carbon sources are important for the maintenance of their tumor-propagating ability. Here we assessed the ability of glycolytic and oxidative murine glioma stem cells (GSCs) to grow in an ultralow glucose medium. Sphere formation assays revealed that exogenous lactate and acetate reversed the growth impair-ment of oxidative GSCs in such medium. Extracellular flux analysis showed that lactate supported oxygen consumption in these cells, whereas metabolomics analysis revealed that it increased the intracellular levels of tricarboxylic acid cycle intermediates, ATP, and GTP as well as increased adenylate and guanylate charge. Lactate also reversed the depletion of choline apparent in the glucose-deprived cells as well as reprogrammed phospholipid and fatty acid biosynthesis. This metabolic reprogramming was associated with a more aggressive phenotype of intracranial tumors formed by lactate-treated GSCs. Our results thus suggest that lactate is an important alternative energetic and biosynthetic substrate for oxidative GSCs, and that it sustains their growth under conditions of glucose deprivation.

  • Heterogeneous Glioma Cell Invasion under Interstitial Flow Depending on Their Differentiation Status

    Namba N., Chonan Y., Nunokawa T., Sampetrean O., Saya H., Sudo R.

    Tissue Engineering - Part A （Tissue Engineering - Part A)  27 （ 7-8 ） 467 - 478 2021年04月

    ISSN  19373341

    　概要を見る

    Glioblastoma (GBM) is the most common and lethal type of malignant brain tumor. A deeper mechanistic understanding of the invasion of heterogeneous GBM cell populations is crucial to develop therapeutic strategies. A key regulator of GBM cell invasion is interstitial flow. However, the effect of an interstitial flow on the invasion of heterogeneous GBM cell populations composed of glioma initiating cells (GICs) and relatively differentiated progeny cells remains unclear. In the present study, we investigated how GICs invade three-dimensional (3D) hydrogels in response to an interstitial flow with respect to their differentiation status. Microfluidic culture systems were used to apply an interstitial flow to the cells migrating from the cell aggregates into the 3D hydrogel. Phase-contrast microscopy revealed that the invasion and protrusion formation of the GICs in differentiated cell conditions were significantly enhanced by a forward interstitial flow, whose direction was the same as that of the cell invasion, whereas those in stem cell conditions were not enhanced by the interstitial flow. The mechanism of flow-induced invasion was further investigated by focusing on differentiated cell conditions. Immunofluorescence images revealed that the expression of cell-extracellular matrix adhesion-associated molecules, such as integrin β1, focal adhesion kinase, and phosphorylated Src, was upregulated in forward interstitial flow conditions. We then confirmed that cell invasion and protrusion formation were significantly inhibited by PP2, a Src inhibitor. Finally, we observed that the flow-induced cell invasion was preceded by nestin-positive immature GICs at the invasion front and followed by tubulin β3-positive differentiated cells. Our findings provide insights into the development of novel therapeutic strategies to inhibit flow-induced glioma invasion. A mechanistic understanding of heterogeneous glioblastoma cell invasion is crucial for developing therapeutic strategies. We observed that the invasion and protrusion formation of glioma initiating cells (GICs) were significantly enhanced by forward interstitial flow in differentiated cell conditions. The expression of integrin β1, focal adhesion kinase, and phosphorylated Src was upregulated, and the flow-induced invasion was significantly inhibited by a Src inhibitor. The flow-induced heterogeneous cell invasion was preceded by nestin-positive GICs at the invasion front and followed by tubulin β3-positive differentiated cells. Our findings provide insights into the development of novel therapeutic strategies to inhibit flow-induced glioma invasion.

  • N-cadherin upregulation mediates adaptive radioresistance in glioblastoma

    Osuka S., Zhu D., Zhang Z., Li C., Stackhouse C.T., Sampetrean O., Olson J.J., Yancey Gillespie G., Saya H., Willey C.D., Van Meir E.G.

    Journal of Clinical Investigation （Journal of Clinical Investigation)  131 （ 6 ）  2021年03月

    ISSN  00219738

    　概要を見る

    Glioblastoma (GBM) is composed of heterogeneous tumor cell populations, including those with stem cell properties, termed glioma stem cells (GSCs). GSCs are innately less radiation sensitive than the tumor bulk and are believed to drive GBM formation and recurrence after repeated irradiation. However, it is unclear how GSCs adapt to escape the toxicity of repeated irradiation used in clinical practice. To identify important mediators of adaptive radioresistance in GBM, we generated radioresistant human and mouse GSCs by exposing them to repeat cycles of irradiation. Surviving subpopulations acquired strong radioresistance in vivo, which was accompanied by a reduction in cell proliferation and an increase in cell-cell adhesion and N-cadherin expression. Increasing N-cadherin expression rendered parental GSCs radioresistant, reduced their proliferation, and increased their stemness and intercellular adhesive properties. Conversely, radioresistant GSCs lost their acquired phenotypes upon CRISPR/Cas9-mediated knockout of N-cadherin. Mechanistically, elevated N-cadherin expression resulted in the accumulation of β-catenin at the cell surface, which suppressed Wnt/β-catenin proliferative signaling, reduced neural differentiation, and protected against apoptosis through Clusterin secretion. N-cadherin upregulation was induced by radiation-induced IGF1 secretion, and the radiation resistance phenotype could be reverted with picropodophyllin, a clinically applicable blood-brain-barrier permeable IGF1 receptor inhibitor, supporting clinical translation.

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  • グリオーマ幹細胞が形成するニッチの成立機構解明と阻害方法の確立

    2019年04月
    -
    2022年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, サンペトラ　オルテア, 基盤研究（Ｃ）, 補助金,  研究代表者

  • グリオーマ幹細胞のニッチ特性の解明とそれを標的とした治療戦略の考案

    2016年04月
    -
    2019年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, サンペトラ，　オルテア, 基盤研究(C), 補助金,  研究代表者

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