The goal of this proposal is to understand how cell competition regulates tissue growth during development and how such mechanisms can be subverted during diseases like cancer. Our lab and other labs have shown that genetic heterogeneity between neighboring populations provokes competitive interactions between them, resulting in the selective elimination of the weaker population (the losers) and the expansion of the stronger one (the winners). During classical cell competition wild-type cells eliminate viable but sub-optimal cells. This type of cell competition functions as a quality control mechanism to selectively remove suboptimal cells from a tissue. During super-competition, cells with higher levels of oncogenes like STAT and Myc kill their wild-type neighbors. Super-competition functions during cancer progression and metastasis. While competitive interactions are conserved and are increasingly well documented, the mechanisms regulating the elimination of the weaker cells or the expansion of the stronger cells are poorly understood. Through next-generation sequencing, we identified two soluble stress-responsive factors that are produced by STAT winners and that promote their competitive fitness. Here, we will test the roles of these factors in cell competition.
Aim 1 is focused on the role of the damage-response pathway in disadvantaging losers or increasing winner fitness in super- competition.
Aim 2 will test the role of extracellular reactive oxygen species in killing losers and/or boosting winner function in both classical cell competition and super-competition. We envision that our studies will elucidate molecular and cellular events employed by pre-cancerous cells to establish themselves within a tissue and that might be operative when these cells progress into fully neoplastic lesions.
Due to evolution, numerous genes exist in very similar forms in other organisms, such as the fruit fly Drosophila. The fruit fly is an excellent genetic organism that has been used with great success to identify and characterize genes critical for basic biological processes. Our study is designed to eludicate how the conserved genes that cause cancer in humans regulate cell competition in Drosophila.
|Herrera, Salvador C; Bach, Erika A (2018) JNK signaling triggers spermatogonial dedifferentiation during chronic stress to maintain the germline stem cell pool in the Drosophila testis. Elife 7:|
|Grmai, Lydia; Hudry, Bruno; Miguel-Aliaga, Irene et al. (2018) Chinmo prevents transformer alternative splicing to maintain male sex identity. PLoS Genet 14:e1007203|
|Cook, Matthew S; Cazin, Coralie; Amoyel, Marc et al. (2017) Neutral Competition for Drosophila Follicle and Cyst Stem Cell Niches Requires Vesicle Trafficking Genes. Genetics 206:1417-1428|
|Anderson, Abigail M; Bailetti, Alessandro A; Rodkin, Elizabeth et al. (2017) A Genetic Screen Reveals an Unexpected Role for Yorkie Signaling in JAK/STAT-Dependent Hematopoietic Malignancies in Drosophila melanogaster. G3 (Bethesda) 7:2427-2438|
|Court, Helen; Ahearn, Ian M; Amoyel, Marc et al. (2017) Regulation of NOTCH signaling by RAB7 and RAB8 requires carboxyl methylation by ICMT. J Cell Biol 216:4165-4182|
|Amoyel, Marc; Hillion, Kenzo-Hugo; Margolis, Shally R et al. (2016) Somatic stem cell differentiation is regulated by PI3K/Tor signaling in response to local cues. Development 143:3914-3925|
|Amoyel, Marc; Anderson, Jason; Suisse, Annabelle et al. (2016) Socs36E Controls Niche Competition by Repressing MAPK Signaling in the Drosophila Testis. PLoS Genet 12:e1005815|
|Amoyel, Marc; Bach, Erika A (2015) MT-Nanotubes: Lifelines for Stem Cells. Cell Stem Cell 17:133-4|
|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|
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