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.
Metastasis causes most cancer deaths, yet it is the least well-understood aspect of cancer biology. It's becoming apparent that in order to understand cancer metastasis, we need to understand early embryo development. Many of the molecular mechanisms used during early embryogenesis are resurrected by cancerous cells during tumor initiation, progression and metastasis. By inducing key embryonic genes, tumorous cells can turn on necessary biological processes to over proliferate, leave the primary site of origin, migrate long distances and grow at distant sites. One such process that plays essential roles both during embryogenesis and in the adult is the evolutionarily conserved JAK/STAT signaling. JAK/STAT signaling is involved in various biological processes including cell proliferation, immunity, cell death and cell migration, so it is not surprising to find mutations in the components of JAK/STAT in various forms of cancer. JAK/STAT signaling is also often implicated in cancer invasion and metastasis but the precise role of this pathway during cell migration is still not well understood. Here, I propose to investigate the role of JAK/STAT signaling during cell migration by using a zebrafish as a model, which is a powerful organism that has been used widely to understand various aspects of human disease such as cancer. The results of this proposal will significantly enhance our understanding of the role of this signaling pathway during cell migration not only during normal development but also during cancer metastasis. In addition, the findings from this study will determine the effects of the JAK/STAT signaling specifically on melanoma development, which will be informative for the development of more effective cancer therapies.
|Hutchins, Erica J; Kunttas, Ezgi; Piacentino, Michael L et al. (2018) Migration and diversification of the vagal neural crest. Dev Biol :|