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Defining the role of Taiman, the Drosophila homolog of AIB1, as a super-competitor in developing epithelia

定义 Taiman（AIB1 的果蝇同源物）作为上皮细胞发育中超级竞争者的作用

基本信息

批准号：
10626071
负责人：
Colby Kristina Schweibenz
金额：
$ 4.77万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10626071
关键词：
Affinity Chromatography Alleles Apoptosis Binding Biochemical Biological Assay Breast Cancer Biology Cell Survival Cells Cessation of life Classification Complex Data Development Diagnosis Disease Dose Drosophila genus Drosophila melanogaster Ecdysone Elements Embryo Ensure Environment Epiblast Epithelial Cells Epithelium Estrogens Genes Genetic Transcription Goals Growth Homologous Gene Hormones Human Immunofluorescence Immunologic Interruption Invaded Knowledge Learning Ligands Link Localized Malignant Neoplasm MYC gene Malignant Neoplasms Measures Mediating Messenger RNA Methods Modeling Modification Molecular NCOA3 gene Neoplasm Metastasis Nuclear Hormone Receptors Oncogene Activation Oncogenes Outcome Pathway interactions Population Process Production Progesterone Proliferating Proteins Proteome Publishing RNA Interference Receptor Signaling Research Ribosomes Role Scientist Signal Transduction System Testing Therapeutic Tissues Transcription Coactivator Translating Tumor Suppressor Proteins United States Wing Woman Work breast cancer progression cancer cell cancer therapy cell type cofactor cost design dosage ecdysone receptor effective therapy experimental study fitness genetic variant hormonal signals insight mRNA Translation malignant breast neoplasm model organism novel novel therapeutics overexpression pro-apoptotic protein receptor statistics steroid hormone steroid hormone receptor tool

项目摘要

PROJECT SUMMARY Invasive breast cancer is a deadly disease, killing ~42,000 women each year and costing the United States over $16.5 billion annually. The complicated disease mechanisms that drive breast cancer are still insufficiently understood to confidently design therapeutics. One mechanism emerging as a potential driver for local invasion in breast and other cancers is ‘cell competition.’ This phenomenon occurs when two different cell populations with different ‘fitness’ levels are juxtaposed in the same tissue. High fitness cells (called ‘winners’) grow more rapidly and kill off slower growing neighbors (called ‘losers’) by apoptosis. Cancer cells acquire ‘winner’ status by activating oncogenes. Oncogenes that confer ‘winner’ status are called ‘super-competitors.’ Our lab uses the model organism, Drosophila melanogaster, to study conserved growth and proliferation pathways that are altered in human cancer. In previous work we showed that Drosophila Taiman (Tai, AIB1 in humans), a co-activator of the Ecdysone steroid hormone receptor (EcR), is a candidate super-competitor and imparts ‘winner’ status to cells via production of the secreted, pro-apoptotic protein Spätzle (Spz), a Toll receptor ligand. We have also shown that Tai binds the Yorkie (Yki) coactivator protein, the main target of the Hippo tumor suppressor pathway, and that Yki:Tai collaboratively drive expression of pro-growth genes. However, we do not fully understand how Tai drives neighbor killing, or whether it requires interactions with EcR and/or Yki. Moreover, classifying Tai as a ‘super-competitor’ requires evidence that lowering the Tai dose confers ‘loser’ status relative to wildtype cells. In the following three Aims, I will test my hypothesis that Tai acts as a super-competitor through either its interaction with Yki (Hippo pathway) or EcR (ecdysone pathway), test the relative fitness of Tai-overexpressing (Taihigh), wildtype (Taiwt), and Tai hypomorphic (Tailow) cells, and carry out experiments to identify cell competition factors regulated by Tai. In Aim 1, I will assess the effects of elevated or reduced Tai on cell survival in homotypic vs. heterotypic environments. To link to our published data, I will also investigate the requirement of the Spz/Toll pathway in these contexts. In Aim 2, I will use candidate-based approaches to test the requirements for Yki/Hippo and EcR signaling in Tai-driven killing of neighbor cells. Finally in Aim 3, I will use the unbiased, discovery-based method Translating Ribosome Affinity Purification with sequencing (TRAP-Seq) to identify the Tai-induced translated proteome in wing cells and candidate ‘competition’ factors within it. These aims will define the molecular mechanisms underlying Tai-regulated cell competition in epithelial tissue. This work could also reveal a link between cell competition and steroid hormone signaling, which could be a novel element of cancer biology. The pathways that will be uncovered by this work will have long-term impacts, as knowledge of cell competition mechanisms could be applied to mammalian models to learn more about cancer emergence and progression. Specifically, knowledge gained from this research could lead to greater understanding of the role of the human homolog AIB1 in breast cancer and lead to the development of potential new therapeutics.

项目总结