Mixed Models in Cell Communication and Cancer

细胞间通讯是多细胞生物体内调节稳态和细胞决策的复杂过程。正确的信息流对于健康的细胞微环境和对外部刺激（如炎症和伤口愈合）的正确反应是必要的。细胞间通讯的改变是衰老和疾病的标志。特别是肿瘤间质相互作用近年来作为公认的治疗干预靶点引起了越来越多的关注.到目前为止，大多数研究都是调查单个细胞因子或分析稳态反馈纠缠细胞间通讯。在这里，我们研究了皮肤细胞的双旁分泌实验设置的细胞间通讯的发病。我们建立了在第一个资助期开发的实验模型系统，并使用条件上清液刺激来记录整个转录组反应时间序列以及整个分泌组的变化，以将细胞因子模式与表型反应相关联。此外，我们通过通信理论的方法，通过独立成分分析和高斯过程的基因表达和细胞因子分泌的变化建模。来自这些通用模型的信息用于使用基因调控网络和布尔模型的机制的全细胞建模，所述布尔模型包括细胞反应的长期动态以及蛋白质信号传导、基因表达和自分泌和旁分泌反馈的多个时间尺度。这些方法将阐明细胞内稳态的双稳定性，将细胞锁定在炎症或迁移状态。最后，我们将通过比较我们目前研究的皮肤通信模型与人黑色素瘤和成纤维细胞的肿瘤-基质相互作用系统来测试通用的调节方案。

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.