Epigenetic Effect of the Microenvironment on Stem Cell Plasticity and Function

微环境对干细胞可塑性和功能的表观遗传效应

• 批准号: 8070504
• 负责人: MARY J.C. HENDRIX
• 金额: $ 32.1万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-03 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8070504
• 关键词: 3-Dimensional; Affect; Biological; Blood Vessels; Cell Fate Control; Cell Line; Cells; Characteristics; Chick Embryo; Communication; Complex; Cues; Data; Development; Disease; Embryo; Epigenetic Process; Gene Expression; Gene Proteins; Genes; Genotype; Goals; Grant; Human; Image; In Situ; Knowledge; Laboratories; Limb structure; Maintenance; Malignant Neoplasms; Melanoma Cell; Metastatic Melanoma; Modeling; Molecular; Multipotent Stem Cells; Mus; Neural Crest; Neural Crest Cell; Neurons; Nodal; Notch Signaling Pathway; Nude Mice; Pathway interactions; Phenotype; Plastics; Play; Population; Process; Property; Qualifying; Research Personnel; Role; Signal Pathway; Signal Transduction; Stem cells; Study models; Testing; Tissues; Translating; Transplantation; UC06; Wound Healing; base; cancer cell; comparative; design; developmental plasticity; extracellular; human embryonic stem cell; insight; laser capture microdissection; melanocyte; melanoma; neoplastic cell; notch protein; novel; novel therapeutics; precursor cell; programs; reconstitution; relating to nervous system; stem cell population; tumor; tumor progression

DESCRIPTION (provided by applicant): One of the most devastating diseases to manage is metastatic melanoma, where the evidence of stem cell subpopulations is starting to emerge. Comparative global gene analyses of aggressive human melanoma cell lines and tumors have revealed the expression of genes associated with multiple cellular phenotypes and precursor stem cells. These findings support the premise that aggressive melanoma cells revert to a multipotent, plastic phenotype. Key to identifying the molecular mechanisms underlying tumor cell plasticity is to elucidate the unique role the microenvironment plays in this process. Most noteworthy are the data we have generated showing the reprogramming of subpopulations (possibly the stem cells) of multipotent metastatic melanoma cells to a melanocyte-like phenotype by the embryonic microenvironment(s) of hESCs and chick neural crest-rich regions. Based on these observations, we propose to test the central hypothesis that the embryonic microenvironments associated with hESCs (Wa01. Wa09 and UC06) and chick neural crest-rich region(s) - contain informational cues with the potential to epigenetically reprogram the genotype and phenotype of human metastatic multipotent melanoma cells exposed to them. Our long term goal is to understand the biological mechanisms underlying the bi-directional communication between stem cells and their microenvironment(s) that ultimately result in cell fate determinations. Our short term goal is to identify the biological and molecular parameters associated with the epigenetic reprogramming of multipotent metastatic melanoma cells exposed to specific hESC environmental cues. Using unique, 3-D organotypic models and chick embryos, together with functional analysis, 4-D imaging, laser capture microdissection, and epigenetic analysis, we propose to: Unchanged Aim 1: Determine the epigenetic influence of the 3-D microenvironment(s) of hESCs for their potential to reprogram the genotype and phenotype of human metastatic multipotent melanoma cells. Revised Aim 2: Identify the molecular basis for the epigenetic reprogramming of the genotype and phenotype of the affected multipotent melanoma cell populations exposed to various hESC 3-D microenvironments, with particular focus on the Nodal signaling pathway. Revised Aim 3: Investigate the developmental plasticity of multipotent melanoma cell populations in an embryonic chick model - to determine the biological relevance of the Nodal signaling pathway involved in stem cell plasticity and the control of cell fate determination and reprogramming of the metastatic phenotype. Lay Summary: At the completion of these studies, we expect to gain new insights into the biological properties of human embryonic and multipotent metastatic melanoma cells with stem cell properties that could be translated for novel therapeutic applications.

描述（由申请人提供）：最具破坏性的疾病之一是转移性黑色素瘤，其中干细胞亚群的证据开始出现。 对侵袭性人黑色素瘤细胞系和肿瘤的比较性全球基因分析揭示了与多种细胞表型和前体干细胞相关的基因表达。 这些发现支持了侵袭性黑色素瘤细胞恢复为多能性、可塑性表型的前提。 确定肿瘤细胞可塑性的分子机制的关键是阐明微环境在这一过程中发挥的独特作用。 最值得注意的是我们已经产生的数据，显示了多能转移性黑素瘤细胞的亚群（可能是干细胞）通过hESC和鸡神经嵴富集区的胚胎微环境重编程为黑素细胞样表型。 基于这些观察结果，我们提出测试中心假设，即与hESC相关的胚胎微环境（Wa 01. Wa 09和UC 06）和鸡神经嵴丰富区-含有信息线索，具有表观遗传学重编程暴露于它们的人转移性多能黑素瘤细胞的基因型和表型的潜力。 我们的长期目标是了解干细胞与其微环境之间双向交流的生物学机制，最终导致细胞命运的决定。 我们的短期目标是确定与暴露于特定hESC环境线索的多能转移性黑色素瘤细胞的表观遗传重编程相关的生物学和分子参数。 使用独特的3-D器官型模型和鸡胚，连同功能分析，4-D成像，激光捕获显微切割和表观遗传分析，我们提出：不变的目标1：确定hESC的3-D微环境的表观遗传影响，以重新编程人类转移性多能黑色素瘤细胞的基因型和表型。 修订目标2：确定暴露于各种hESC 3-D微环境的受影响多能黑色素瘤细胞群体的基因型和表型的表观遗传重编程的分子基础，特别关注Nodal信号通路。 修订目标3：研究鸡胚胎模型中多能黑色素瘤细胞群的发育可塑性-以确定参与干细胞可塑性的Nodal信号通路的生物学相关性以及细胞命运决定和转移表型重编程的控制。 简单总结：在这些研究完成后，我们希望获得新的见解，人类胚胎和多能转移性黑色素瘤细胞的干细胞特性，可以转化为新的治疗应用的生物学特性。

项目成果

Cancer hallmarks in induced pluripotent cells: new insights.

• DOI: 10.1002/jcp.22280
• 发表时间: 2010-11
• 期刊: JOURNAL OF CELLULAR PHYSIOLOGY
• 影响因子: 5.6
• 作者: Malchenko, Sergey;Galat, Vasiliy;Seftor, Elisabeth A.;Vanin, Elio F.;Costa, Fabricio F.;Seftor, Richard E. B.;Soares, Marcelo B.;Hendrix, Mary J. C.
• 通讯作者: Hendrix, Mary J. C.

Potential for the embryonic morphogen Nodal as a prognostic and predictive biomarker in breast cancer.

• DOI: 10.1186/bcr3185
• 发表时间: 2012-05-11
• 期刊: Breast cancer research : BCR
• 作者: Strizzi L;Hardy KM;Margaryan NV;Hillman DW;Seftor EA;Chen B;Geiger XJ;Thompson EA;Lingle WL;Andorfer CA;Perez EA;Hendrix MJ
• 通讯作者: Hendrix MJ

Melanoma tumor cell heterogeneity: a molecular approach to study subpopulations expressing the embryonic morphogen nodal.

黑色素瘤肿瘤细胞异质性：一种研究表达胚胎形态淋巴结的亚群的分子方法。

• DOI: 10.1053/j.seminoncol.2014.02.001
• 发表时间: 2014-04
• 期刊: Seminars in oncology
• 影响因子: 4
• 作者: Seftor EA;Seftor REB;Weldon D;Kirsammer GT;Margaryan NV;Gilgur A;Hendrix MJC
• 通讯作者: Hendrix MJC

Reprogramming multipotent tumor cells with the embryonic neural crest microenvironment.

• DOI: 10.1002/dvdy.21613
• 发表时间: 2008-10
• 期刊: DEVELOPMENTAL DYNAMICS
• 影响因子: 2.5
• 作者: Kasemeier-Kulesa, Jennifer C.;Teddy, Jessica M.;Postovit, Lynne-Marie;Seftor, Elisabeth A.;Seftor, Richard E. B.;Hendrix, Mary J. C.;Kulesa, Paul M.
• 通讯作者: Kulesa, Paul M.

Nodal expression and detection in cancer: experience and challenges.

• DOI: 10.1158/0008-5472.can-11-3419
• 发表时间: 2012-04-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Strizzi L;Hardy KM;Kirschmann DA;Ahrlund-Richter L;Hendrix MJ
• 通讯作者: Hendrix MJ