Role of Missing Metastasis Gene in tumor progression

缺失转移基因在肿瘤进展中的作用

• 批准号: 8297358
• 负责人: Steven ZHAN
• 金额: $ 26.46万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8297358
• 关键词: Actins; Adhesions; Adhesiveness; Age; Animal Model; Antigens; Apoptosis; Attention; B cell differentiation; B lymphoid malignancy; B-Cell Lymphomas; B-Lymphocytes; Bone Marrow; CXCL13 gene; Cancer Intervention; Cell Adhesion Molecules; Cell Communication; Cell Lineage; Cell Maturation; Cell Polarity; Cell membrane; Cells; Chemotaxis; Communication; Cytoskeleton; Defect; Development; Disadvantaged; Elements; Endocytosis; Event; Extracellular Matrix; Family; Fibroblasts; Funding; Future; Genes; Goals; Grant; Growth Factor; Human; In Vitro; Inflammation; Knockout Mice; Laboratories; Light; Link; Lymphocyte; Lymphoid; Lymphoma; Lymphomagenesis; MYC gene; Malignant - descriptor; Malignant Neoplasms; Mechanics; Mediating; Membrane; Monomeric GTP-Binding Proteins; Mouse Strains; Mus; Neoplasm Metastasis; Oncogenic; Organ; Peripheral; Phenotype; Phosphotransferases; Physiological; Play; Predisposition; Property; Protein Tyrosine Kinase; Proteins; Reaction; Recruitment Activity; Role; Screening procedure; Series; Shapes; Signal Pathway; Signaling Molecule; Spleen; Splenomegaly; Stem cells; Stimulus; Stress Fibers; Stromal Cells; Surface; Tertiary Protein Structure; Testing; Transplantation; cancer cell; cancer therapy; cell behavior; cell motility; cell stroma; chemokine; chemokine receptor; cytokine; design; extracellular; in vivo; lymphoid neoplasm; member; mutant; neoplastic cell; novel; overexpression; progenitor; receptor internalization; response; rho; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): The long-term goal of this grant is to elucidate a mechanic link responsible for aberrant responses of stem cells/progenitors or cancer initiating cells to their microenvironments. The immediate goal is to determine the physiological and pathological role of the missing in metastasis (MIM or MTSS1) gene in B lymphocytes and B-cell lymphomas. Previous studies from our lab and others have shown that MIM belongs to the family of inverse BAR-domain proteins that shapes the membrane curvature and regulates cellular polarity, endocytosis, cell motility and reorganization of the actin cytoskeleton. MIM is also frequently aberrantly expressed in various metastatic and advanced malignant cells. However, the pathological relevance of aberrant MIM expressions to malignant progression has not yet been established because of the lack of a proper animal model. We have recently found that MIM is the only I-BAR gene that is abundantly expressed in normal human and murine B lymphocytes but markedly underexpressed in a series of primary and established B lymphocytic malignant cells. We have recently established a MIM knockout mouse strain and observed that the majority of the null MIM mice developed spontaneous B-cell lymphomas within two years along with development of enlarged spleens. Preliminary study indicated several defects associated with null MIM B lineage cells: they were abnormally distributed in the bone marrow, poorly recruited to the spleen, impaired in chemotactic responses to chemokine CXCL13, deficient in the internalization of the receptor of CXCL13, and unable to polarize after stimulatio with chemokines. Furthermore, we observed that null MIM cells displayed significantly altered shapes, reduced adhesiveness to extracellular matrix and the formation of actin stress fibers. Therefore, we hypothesize that MIM plays an important role in the interaction between B lineage cells and stroma during B-cell differentiation in different lymphoid organs, and that a disturbed interaction underlies the promoting of the lymphomagenesis in MIM knockout mice. To test this hypothesis, we have planned a series of studies with three specific aims: (1) characterization of the physiological role of MIM in B lymphocytes, (2) characterization of the role of MIM deficiency in lymphomagenesis, and (3) characterization of the signaling pathway of MIM in B cells. We anticipate that accomplishment of these aims will shed light on the mechanistic link for B lineage cells to interact with their microenvironments and to progress into malignances. Because MIM represents a signaling pathway distinct from previously characterized circuits for tumorigenesis, we also expect that our study will explore new targets that may be used in cancer interventions in the future. PUBLIC HEALTH RELEVANCE: The proposed study will characterize a mouse strain in which the gene for missing in metastasis has been disrupted. We will use this animal model to explore the mechanism by which MIM deficiency induces tumor formation.

描述（由申请人提供）：本资助的长期目标是阐明干细胞/祖细胞或癌症起始细胞对其微环境的异常反应的机制联系。当前的目标是确定B淋巴细胞和B细胞淋巴瘤中转移缺失（MIM或MTSS1）基因的生理和病理作用。我们实验室和其他人之前的研究表明，MIM属于逆bar结构域蛋白家族，它塑造膜曲率并调节细胞极性、内吞作用、细胞运动和肌动蛋白细胞骨架的重组。MIM也经常在各种转移性和晚期恶性细胞中异常表达。然而，由于缺乏适当的动物模型，异常MIM表达与恶性进展的病理相关性尚未建立。我们最近发现，MIM是唯一在正常人和小鼠B淋巴细胞中大量表达的I-BAR基因，但在一系列原发性和已建立的B淋巴细胞恶性细胞中明显表达不足。我们最近建立了一个MIM敲除小鼠品系，并观察到大多数没有MIM的小鼠在两年内随着脾脏增大而发生自发性b细胞淋巴瘤。初步研究表明，与无效的MIM B系细胞相关的几个缺陷：它们在骨髓中分布异常，很少募集到脾脏，对趋化因子CXCL13的趋化反应受损，CXCL13受体内化不足，在趋化因子刺激后无法极化。此外，我们观察到无MIM细胞的形状明显改变，对细胞外基质的粘附性降低，肌动蛋白应力纤维的形成。因此，我们假设在不同淋巴器官的B细胞分化过程中，MIM在B系细胞和基质之间的相互作用中起着重要作用，并且在MIM敲除小鼠中，受干扰的相互作用是促进淋巴瘤发生的基础。为了验证这一假设，我们计划了一系列的研究，有三个特定的目的：(1)表征MIM在B淋巴细胞中的生理作用，(2)表征MIM缺乏在淋巴瘤发生中的作用，(3)表征B细胞中MIM的信号通路。我们预计这些目标的实现将揭示B系细胞与其微环境相互作用并进展为恶性肿瘤的机制联系。由于MIM代表了一种不同于先前表征的肿瘤发生回路的信号通路，我们也期望我们的研究将探索未来可能用于癌症干预的新靶点。