RhoA function in Intestinal Epithelial Cells as a key element in Colorectal Cancer

基于我们以前的研究，我们认为RhoA在小肠上皮细胞（IEC）中是细胞骨架修复和维持肠道稳态的关键驱动因素。另一方面，RhoA被认为是一种癌症生物标志物，因为它的激活有助于癌症的发生，以及肿瘤的生长和恶性行为。然而，我们自己的初步数据表明，抑制RhoA功能的小鼠缺乏上皮RhoA（RhoAΔIEC）导致自发性结肠肿瘤的发生。总之，该项目的关键假设是，在结肠直肠癌（CRC）的背景下，IEC内RhoA依赖性细胞因子重排以及RhoAΔIEC小鼠中的皮下炎症作为肿瘤生长的驱动因子和调节因子。总之，我们认为，RhoA在小肠上皮中的体内功能的分析可能提供有关肠道内稳态和肿瘤形成的相关信息。在本项目中，我们的目标是在大肠癌的背景下，在缺乏上皮RhoA的情况下，识别自发性肿瘤发生背后的分子机制。我们将集中讨论两个主要的科学问题：RhoA缺陷IEC中结肠限制性上皮改变导致自发性肿瘤发生;以及炎症作为RhoAΔIEC小鼠肿瘤生长的驱动剂和调节剂的作用。最后，我们打算通过研究患者样本，将我们的研究结果应用于存在或不存在结肠炎的CRC患者。我们的研究结果将有助于了解CRC发病机制所需的机制知识。我们相信，对RhoA通路作用的基础研究将有助于深入了解CRC的分子发病机制，并有望为CRC患者的新治疗方法铺平道路。

Based on our previous study, we believe that RhoA within intestinalepithelial cells (IECs) is a key driver of cytoskeleton rearrangementand maintenance of intestinal homeostasis. On the other hand, RhoAhas been postulated as a cancer biomarker, since its activationcontributes to cancer initiation, as well as tumor growth and malignantbehavior. However, our own preliminary data demonstrate thatinhibition of RhoA function in mice lacking epithelial RhoA(RhoAΔIEC) causes spontaneous colonic tumorigenesis. Together,the key hypothesis of the project is that RhoA-dependent cytoskeletonrearrangement within IECs together with the subjacent intestinalinflammation in RhoAΔIEC mice act as drivers and modulators oftumor growth in the context of Colorectal Cancer (CRC). Altogether,we think that the analysis of the in vivo function of RhoA in intestinalepithelium might provide relevant information about homeostasis andtumor formation in the gut. In the present project, we would then aimat the identification of the molecular mechanism behind spontaneoustumorigenesis in the absence of epithelial RhoA in the context ofCRC. We will focus on two main scientific questions: thecolonrestricted epithelial alterations in RhoA-deficient IECs leading tothe spontaneous tumorigenesis; and the role of inflammation as driverand modulator of tumor growth in RhoAΔIEC mice. Finally, we intendto translate our findings to patients with CRC in the presence orabsence of colitis by studying patient samples. Our findings willcontribute to the mechanistic knowledge required for theunderstanding of CRC pathogenesis. We believe that basic researchon the role of the RhoA pathway will allow insights into the molecularpathogenesis of CRC and hopefully pave the way for new therapeuticapproaches for patients with CRC.