Mixed Models in Cell Communication and Cancer

点击翻译按钮获取中文摘要

Cell-Cell Communication is a complex process regulating thehomeostasis and cellular decisions in a multicellular organism. Thecorrection information flow is a necessity for a healthy cellularmicroenvironment and proper response to external stimuli, such asinflammation and wound healing. Altered cell-cell communication is ahallmark of aging and disease. In particular tumor stroma interactionshave attracted increased attention in recent years as putativetherapeutic targets of intervention. Most studies so far haveinvestigated individual cytokines or analyzed steady statefeedback-entangled cell-cell communication. Here we study the onset ofcell-cell communication by a defined double paracrine experimentalsetup of skin cells. We build in the experimental model systemsdeveloped in the first funding period and use conditioned supernatantstimulation to record whole transcriptome response time series as wellas changes in the whole secretome to correlate cytokine patterns withphenotype responses. Moreover, we model the changes in gene expressionand cytokine secretion through communication theoretic approachesthrough independent component analysis and Gaussian processes. Theinformation from these general models is used for mechanistic, wholecell modeling using gene regulatory networks and Boolean models thatcomprise long-term dynamics of the cellular responses as well asmultiple time scales of protein signaling, gene expression and auto-and paracrine feedbacks. Such approaches will elucidate bi-stabilityof cellular homeostasis locking the cells into inflammatory ormigratory states. Lastly, we will test the generic regulatoryschemes by comparison of our currently investigated skin communicationmodel with a tumor-stroma interaction system of human melanoma andfibroblast cells.