SFB 850: Control of Cell Motility in Morphogenesis, Cancer Invasion and Metastasis

尽管癌症研究取得了重大进展，但肿瘤转移仍然是癌症相关死亡的主要原因。转移级联的许多步骤是建立在胚胎发生、器官发生和组织再生中运作的生物过程的异常再激活上的。CRC 850研究细胞粘附和细胞基质相互作用作为胚胎发生和癌症中细胞运动的先决条件的变化。对细胞运动的不同模式的研究一直是研究的重点。细胞剥离和侵袭的发生以及细胞迁移的方式是由细胞的内在特性决定的。在癌细胞中，遗传程序的改变（epi），例如由致癌突变触发，可以诱导细胞粘附减少和细胞运动性增加。癌细胞行为的这些变化不像迄今所预期的那样受到细胞内在致癌信号的严格调节。微环境刺激可以调节这些致癌信号，使癌细胞在成功定植于外源组织后恢复高移动性和侵袭性。癌细胞在上皮和间充质状态之间的动态转换，即上皮到间充质和间充质到上皮的转变（EMT和MET），为治疗干预提供了机会，因为从一种状态到另一种状态的转变改变了假定的药物靶点的表达，并影响了癌细胞的增殖和自我更新能力。CRC 850将分析细胞可塑性背景下细胞运动的不同模式，以及在发育过程和癌症进展和侵袭过程中微环境的影响。为了反映该领域的巨大进步，我们决定将新的方面纳入我们合作研究中心现有的研究领域。将癌细胞的表观遗传状态及其微环境因素的动态调控与癌细胞的粘附和迁移特性联系起来是当前研究的一个新热点。这种方法有很大的潜力转化为临床，因为表观遗传修饰剂在许多情况下是可用药的。在癌症治疗方面，肿瘤微环境现在被认为是化疗、基于激酶抑制剂的靶向治疗和免疫治疗的临床反应的关键调节剂。因此，通过包括研究免疫细胞进入癌症以及小鼠癌症模型中的炎症反应的项目，这些方面得到了加强。这些项目将得到新的成像技术的大力支持，其中结合活体显微镜和免疫细胞和细胞外基质成分的遗传标记，可以实时分析动态微环境。

Despite significant advances in cancer research and oncology metastasis remains the leading cause of cancer-related death. Many steps of the metastatic cascade are built on the aberrant reactivation of biological processes operative in embryogenesis, organogenesis and tissue regeneration. The CRC 850 studies changes in cell-cell adhesion and cell-matrix interactions as a prerequisite for cell motility in embryogenesis and cancer. Investigations on different modes of cellular motility have been in the focus of research. Initiation of cellular delamination and invasion as well as the mode of cellular migration are preset by cell intrinsic properties. In cancer cells altered (epi)genetic programs, e.g. triggered by oncogenic mutations, can induce reduction of cellular adhesion and increase cellular motility. These changes of cancer cell behavior are less stringently regulated by cell intrinsic oncogenic signaling as hitherto anticipated. Microenvironmental stimuli can modulate these oncogenic signals to revert the high mobility and invasiveness of cancer cells once they successfully colonized a foreign tissue. The dynamic switch of cancer cells between epithelial and mesenchymal states, i.e. epithelial-to-mesenchymal and mesenchymal-to-epithelial transition (EMT and MET), provides an opportunity for therapeutic intervention, as the transition from one state to the other alters the expression of putative drug targets and affects the proliferative and self-renewing capacity of cancer cells. The CRC 850 will analyze the different modes of cell motility in the context of cell plasticity and with respect to the influence of the microenvironment during developmental processes and cancer progression and invasion. To reflect the tremendous progress in the field, we decided to incorporate novel aspects into the already existing lines of research in our collaborative research center. One new focus of several projects is to link the epigenetic state of cancer cells and its dynamic regulation by microenvironmental factors to the adhesive and migratory properties of cancer cells. This approach has great potential for translation into the clinic, since epigenetic modifiers are in multiple cases druggable. Concerning cancer therapy, the tumor microenvironment is now recognized as a critical modulator for clinical responses to chemotherapy, kinase-inhibitor based targeted therapy and immunotherapy. Hence, these aspects have been strengthened by including projects investigating the movements of immune cells into cancers as well as inflammatory responses in murine cancer models. These projects will be strongly supported by novel imaging technologies in which the combination of intra-vital microscopy and the genetic labeling of immune cells and extracellular matrix components allow for the real-time analysis of the dynamic microenvironments.