The molecular mechanisms controlling cell competition hold great potential for advances in treating growth deficiencies, in cancer biology and in regenerative medicine. Cell competition is a quality-control mechanism to insure that the only the """"""""fittest"""""""" cells contribute to the adult organism. It shares many properties with the early stages of cancer, in which transformed cells with elevated metabolic rates take over a field of wild-type cells. Cell competition is induced along the interface of adjacent cell populations that differ in metabolic rates: cells with the higher growth rate (winners) reproduce at the expense of those with the lower one (losers). Work in Drosophila has shown that over-expression of dmyc, the sole fly homolog of the human oncogene c-myc that is re-arranged in many tumors, confers winner status on cells, and this is strongly correlated with inducing de novo ribosome biogenesis. The work in this proposal shows that sustained activation of the JAK/STAT signaling pathway causes cells to become winners that grow at the expense of their loser neighbors, while reduction in pathway activity imparts """"""""loser"""""""" status, resulting in elimination. Hyper-activation of the four JAKs or seven STATs causes several human cancers. There is a single JAK and a single STAT (called Stat92E) in Drosophila, and this lack of genetic redundancy makes Drosophila an ideal system in which to address the role of this pathway in cell competition. The preliminary data in this application show that Stat92E does not function through dMyc and vice versa. Furthermore, unlike dMyc, hyper-active Stat92E does not induce ribosome biogenesis. However, winners expressing hyper-active Stat92E or elevated dMyc cause the death of losers located several cell diameters away. These results demonstrate that activated Stat92E is a super-competitor and strongly suggest that Stat92E and dMyc operate independently and converge on common target genes encoding soluble proteins that cause death in losers. The broad, long-term objectives of this application are to determine the molecular mechanisms of competition used by winners with increased activity of the JAK/STAT pathway. Genome-wide expression profiling will be used to identify target genes that have altered expression in winners with hyper-active Stat92E as compared to controls (Aim 1). A clonal growth assay in the Drosophila wing disc will be used to generate winners that express hyper-active Stat92E but lack the candidate gene and then to determine if these cells can still kill losers located several cell diameters away (Aim 2). The goals of this application are extremely pertinent to the mission of the NICHD, one of which is """"""""learning about growth and development,"""""""" as the experiments in this proposal will likely uncover genes required for normal growth and that may be co-opt by transformed cells.
Due to evolution, jak and stat genes exist in very similar forms in other organisms, such as the fruit fly Drosophila. The fruit fly is an excellent genetic organis that has been used for many years in research laboratories and with great success to identify and characterize genes critical for basic biological processes. Our study is designed to eludicate how the JAK/STAT pathway regulates cell competition in Drosophila.
| Amoyel, Marc; Anderson, Abigail M; Bach, Erika A (2014) JAK/STAT pathway dysregulation in tumors: a Drosophila perspective. Semin Cell Dev Biol 28:96-103 |
| Amoyel, Marc; Simons, Benjamin D; Bach, Erika A (2014) Neutral competition of stem cells is skewed by proliferative changes downstream of Hh and Hpo. EMBO J 33:2295-313 |
| Amoyel, Marc; Bach, Erika A (2014) Cell competition: how to eliminate your neighbours. Development 141:988-1000 |
| Amoyel, Marc; Sanny, Justina; Burel, Michael et al. (2013) Hedgehog is required for CySC self-renewal but does not contribute to the GSC niche in the Drosophila testis. Development 140:56-65 |
| Rodrigues, Aloma B; Zoranovic, Tamara; Ayala-Camargo, Aidee et al. (2012) Activated STAT regulates growth and induces competitive interactions independently of Myc, Yorkie, Wingless and ribosome biogenesis. Development 139:4051-61 |
