Role of JAK/Stat signaling during zebrafish neural crest delamination and migration

 描述（由申请人提供） 转移是癌症患者死亡的主要原因，但我们未能了解这一过程的基本机制，以开发有效的治疗方法来干扰其进展。肿瘤经常使用的一种机制是它们能够劫持胚胎程序，以增加它们的可塑性，从而离开原发性肿瘤，长距离迁移并在远处生长。为了实现这一目标，癌细胞诱导胚胎基因开启在细胞粘附、迁移和增殖中发挥作用的信号通路。在胚胎发生和成体中起重要作用的一种这样的途径是进化上保守的JAK/STAT途径。JAK/STAT信号转导参与多种生物学过程，包括增殖、免疫、凋亡和细胞迁移，并且还常常涉及癌症转移。然而，其在细胞迁移和转移过程中的确切作用仍然没有很好地理解。为了了解这一途径在细胞迁移过程中的确切作用，我将使用斑马鱼神经嵴迁移作为体内模型。鉴于这些胚胎细胞和侵袭性肿瘤细胞之间的显着相似性，这也有望提供一个强大的体内模型来研究癌症转移。首先，我将确定相关的JAK/STAT通路组件在神经嵴迁移。然后，我将分离下游JAK/STAT靶基因和其他相互作用在神经嵴迁移。最后，我将测试JAK/STAT通路对黑色素瘤的特异性影响。这一建议的结果将显着提高我们对这一途径在细胞迁移过程中的作用的理解，无论是在正常发育和癌症转移。此外，本研究的结果将确定JAK/STAT信号传导对黑色素瘤发展的特异性影响。

 DESCRIPTION (provided by applicant) Metastasis is the leading cause of death in cancer patients, yet we fail to understand the fundamental mechanisms of this process to develop effective therapies to interfere with its progression. One mechanism that tumors use frequently is their ability to hijack embryonic programs to increase their plasticity to leave the primary tumor, migrate long distances and grow at distant sites. To achieve this, cancerous cells induce embryonic genes to turn on signaling pathways that play roles in cell adhesion, migration, and proliferation. One such pathway that plays essential roles both during embryogenesis and in the adult is the evolutionarily conserved JAK/STAT pathway. JAK/STAT signaling is involved in various biological processes including proliferation, immunity, apoptosis and cell migration and is also often implicated cancer metastasis. However, its precise role during cell migration and metastasis is still not well understood. In order to understand the precise role of this pathway during cell migration, I will use zebrafish neural crest migration as an in vivo model. Given the remarkable similarities between these embryonic cells and invasive tumor cells, this also holds the promise of providing a powerful in vivo model to study cancer metastasis. First, I will identif the relevant JAK/STAT pathway components during neural crest migration. Then I will isolate downstream JAK/STAT target genes and other interactors during neural crest migration. Lastly, I will test the effects of the JAK/STAT pathway specifically on melanoma. The results of this proposal will significantly enhance our understanding of the role of this pathway during cell migration both during normal development and cancer metastasis. In addition, the findings from this study will determine the effects of the JAK/STAT signaling specifically on melanoma development.