Role of Missing Metastasis Gene in Tumor Progression

描述(由申请人提供)：这项资助的长期目标是阐明干细胞/祖细胞或癌症启动细胞对其微环境的异常反应的机制联系。近期的目标是确定转移中缺失基因(MIM或MTSS1)在B淋巴细胞和B细胞淋巴瘤中的生理和病理作用。我们实验室和其他实验室以前的研究表明，MIM属于反向杆域蛋白家族，它塑造细胞膜的曲率，并调节细胞的极性、内吞作用、细胞运动和肌动蛋白细胞骨架的重组。MIM也经常在各种转移和晚期恶性细胞中异常表达。然而，由于缺乏合适的动物模型，MIM异常表达与恶性进展的病理相关性尚未确定。我们最近发现，MIM是唯一一个在正常人类和小鼠B淋巴细胞中大量表达的I-bar基因，但在一系列原代和已建立的B淋巴细胞恶性肿瘤细胞中明显低表达。我们最近建立了一个MIM基因敲除小鼠品系，并观察到大多数MIM基因缺失的小鼠在两年内出现自发性B细胞淋巴瘤，并伴随着脾增大的发展。初步研究表明，缺失MIM B系细胞有几种缺陷：它们在骨髓中分布异常，在脾中的募集能力较差，对趋化因子CXCL13的趋化反应受损，CXCL13受体内化不足，在趋化因子刺激后不能极化。此外，我们观察到空MIM细胞的形状发生了显著变化，与细胞外基质的粘附性降低，肌动蛋白应激纤维的形成也减少。因此，我们推测在不同淋巴器官中B细胞分化过程中，MIM在B细胞与基质的相互作用中起着重要作用，而这种紊乱的相互作用是促进MIM基因敲除小鼠淋巴肿大的基础。为了验证这一假设，我们计划了一系列研究，目的有三个：(1)确定MIM在B淋巴细胞中的生理作用；(2)确定MIM缺陷在淋巴肿瘤发生中的作用；(3)确定MIM在B细胞中的信号通路。我们预计，这些目标的实现将有助于阐明B系细胞与其微环境相互作用并进展为恶性肿瘤的机制。由于MIM代表了一种不同于以前描述的肿瘤发生通路的信号通路，我们也预计我们的研究将探索未来可能用于癌症干预的新靶点。

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.