Control of immune cell infiltration into tumors by endothelial Notch signaling

癌症是一种遗传性疾病，大多数研究仍然集中在癌细胞的改变上。然而，癌细胞的生长与其微环境密切相关。间质对肿瘤细胞的反应（例如免疫细胞浸润、血管生成和细胞外基质的产生）是宿主防御程序的一部分，但不幸的是，这种间质重编程的几个方面支持肿瘤进展和转移。此外，越来越多的证据表明，微环境实质上有助于转移性疾病对化疗的抵抗。这强调了迫切需要更好地了解癌细胞和周围基质细胞之间的双向相互作用，以最终开发更好的治疗方法。在这个项目中，我们将解决癌症进展过程中内皮细胞与免疫细胞和癌细胞之间的串扰。该项目的灵感来自于我们观察到人类肿瘤样本的肿瘤血管中Notch信号传导活性增加。我们以前的数据表明，Notch配体经常在肿瘤细胞上表达，但也在肿瘤浸润性中性粒细胞上表达，其可以激活内皮细胞上的Notch 1受体。我们已经建立了大量的方法、动物模型和未发表的数据，表明持续的内皮Notch信号转导促进肿瘤细胞穿过血管壁的迁移和骨髓细胞浸润到肿瘤中。因此，内皮Notch信号传导改变转录组，这导致促炎性衰老样表型。这包括趋化因子如CCL2和粘附因子如VCAM 1的分泌。这些蛋白质促进肿瘤细胞迁移和髓样细胞浸润到肿瘤中。此外，内皮Notch信号传导促进循环肿瘤细胞的归巢。因此，我们的初步数据表明，持续的内皮Notch信号促进转移。我们的目标是破译如何操纵内皮细胞中的Notch信号活性影响免疫细胞浸润和肿瘤进展的机制。因此，我们将利用细胞培养系统和小鼠模型来诱导内皮细胞特异性Notch功能的获得和丧失。这些研究中的大多数将在晚期卵巢癌模型中进行。该模型允许区分Notch介导的对免疫细胞浸润和肿瘤血管生成的作用。最终目标将是解读内皮Notch抑制是否是限制肿瘤进展和转移扩散的新型治疗工具。

Cancer is a genetic disease and most research is still focused on alterations in cancer cells. However, cancer cells grow in close interaction with their microenvironment. The stromal response to tumor cells (e.g. immune cell infiltration, angiogenesis and generation of extracellular matrix) is part of the host defense program, but unfortunately several aspects of this stromal reprogramming support tumor progression and metastasis. Furthermore, there is increasing evidence that the microenvironment substantially contributes to resistance against chemotherapy in metastatic disease. This emphasizes the urgent need for better understanding the bi-directional interactions between cancer cells and surrounding stromal cells to ultimately develop better therapies. In this project we will address the crosstalk between endothelial cells with immune and cancer cells during cancer progression. This project was inspired by our observation of increased Notch signaling activity in tumor blood vessels of human tumor samples. Our previous data show that Notch ligands are frequently expressed on tumor cells but also on tumor-infiltrating neutrophils, which can activate Notch1 receptors on endothelial cells. We have established a large repertoire of methods, animal models and unpublished data showing that sustained endothelial Notch signaling facilitates the transmigration of tumor cells through blood vessel walls and the infiltration of myeloid cells into tumors. Thereby, endothelial Notch signaling changes the transcriptome, which leads to a pro-inflammatory, senescent-like phenotype. This includes secretion of chemokines like CCL2 and adhesion factors like VCAM1. These proteins facilitate tumor cell transmigration and myeloid cell infiltration into tumors. Furthermore, endothelial Notch signaling promoted the homing of circulating tumor cells. As such our preliminary data showed that sustained endothelial Notch signaling promotes metastasis.We aim at deciphering the mechanisms how manipulation of Notch signaling activity in endothelial cells influences infiltration of immune cells and tumor progression. Therefore we will make use of cell culture systems and mouse models for inducible endothelial cell-specific Notch gain and loss of function. Most of these studies will be performed in a model of advanced stage ovarian carcinoma. This model allows the distinction of Notch-mediated effects on immune cell infiltration and tumor angiogenesis. The ultimate goal will be to decipher if endothelial Notch inhibition is a novel therapeutic tool to limit tumor progression and metastatic spreading.