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

• Applicant: Privatdozentin Dr. Rocío López Posadas, Ph.D.
• Subject Area: Gastroenterology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 461063481

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.

• DFG Programme: Research Grants