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.
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.
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