Hedgehog-mediated regulation of cell adhesion

描述（由申请人提供）：动物发育中的组织模式需要促进和维持不同细胞群物理分离的粘附机制。许多旁分泌形态原信号被提出用于指定细胞亲和性的差异和形成尖锐和稳定的边界，这反过来又用于维持组织生长过程中形态原组织者的位置和形状。该项目的长期目标是了解Hedgehog （Hh）信号定义特定细胞亲和力并导致Hh-分泌（无应答）细胞和Hh-应答（无分泌）细胞分离的细胞和分子机制。越来越多的证据表明，某些人类癌细胞分泌的Hh可能向周围组织发出信号，促进肿瘤的生长和转移。此外，恶性侵袭可能被认为是一个正常的细胞分离的过程，在这个过程中癌细胞和组织细胞之间存在交叉粘附。因此，这项研究不仅有助于我们对组织模式的分子和细胞基础的认识，以及对Hh信号通路本身的进一步理解，而且还将揭示癌症进展的机制，可能导致发现新的癌症治疗靶点。

DESCRIPTION (Provided by Applicant): Tissue patterning in animal development requires adhesive mechanisms that promote and maintain physical segregation of different cell populations. Many paracrine morphogen signals have been proposed to specify the differences in cell affinity and the formation of sharp and stable boundaries which, in turn, serve to maintain the position and shape of morphogen organizers during the growth of a tissue. The long-term goal of this project is to understand the cellular and molecular mechanisms by which the Hedgehog (Hh) signal defines specific cell affinities and lead to the segregation of Hh-secreting (non-responding) cells and Hh-responding (non-secreting) cells. Increasing evidence indicates that Hh secreted by certain human cancer cells may signal to surrounding tissue and promote tumor growth and metastasis. Furthermore, malignant invasion might be considered a normal process of cell segregation in reverse, in which there is cross-adhesion between cancer cells and tissue cells. Therefore, this study will not only contribute significantly to our knowledge of the molecular and cellular bases of tissue patterning as well as further understanding of the Hh signal pathway per se, but will also shed light on the mechanisms of cancer progression, perhaps leading to the discovery of new therapeutic targets in cancers. The Drosophila wing imaginal disc is subdivided into an anterior (A) and a posterior (P) compartment. P cells secrete Hh and, at the same time, are refractory to the Hh signal. In contrast, A cells can receive and respond to Hh, but do not express Hh by themselves. The cells of the two compartments do not intermingle during development. However, A cells unable to respond to the Hh signal no longer segregate from P cells. The current view is that the response to the Hh signal induces a change in the adhesiveness and that this difference leads to the segregation of A cells from P cell. Combining this model genetic system with broad experimental approaches that incorporate powerful biochemical, molecular, and cellular techniques, the investigator proposes: 1) to investigate how the Hh signal directly alters the affinity differences between Hh-secreting P cells and Hh- responding A cells by modulating cell surface levels of the Ihog family proteins; 2) to identify additional cell adhesion molecules involved in regulating A/P cell segregation; and 3) to determine whether and how the Shh signal alters cell affinity by regulating expression levels of the vertebrate Ihog homologues. PROJECT NARRATIVE: Increasing evidence indicates that Hedgehog (Hh) secreted by certain human cancer cells may signal to surrounding tissue and promote tumor growth and metastasis. Furthermore, malignant invasion might be considered a normal process of cell segregation in reverse, in which there is cross-adhesion between cancer cells and tissue cells. Therefore, this study, mechanisms by which the Hh signal defines specific cell adhesion, will not only contribute significantly to our knowledge of the molecular and cellular bases of tissue patterning and further understanding of the Hh signal pathway, but will also shed light on the mechanisms of cancer progression, perhaps leading to the discovery of new therapeutic targets in cancers.