Obiettivo An association between inflammation and carcinogenesis is well established, however, how they are related mechanistically in subtypes of sporadic intestinal tumours remains unclear. This study aims to decipher how oncogenes determine the inflammatory microenvironment (stroma) and how this affects tumour development and survival. Notably, intestinal epithelium-specific expression of oncogenic Kras(G12D), Braf(V637E) and Pik3ca(H1047R) in mice mimics serrated intestinal cancers in humans faithfully. Preliminary data suggest that the mutational make-up of the tumour may dictate the pro- and anti-tumourigenic immune response, which in turn determines tumour development and survival. This study therefore aims to characterise the tumour-infiltrating immune cells by systematic immunophenotyping and to decipher the involved inflammatory signalling mechanisms in a cell-type and mutation-specific manner. Moreover, we aim to reconstruct the formation of the oncogene-specific inflammatory microenvironment, which we will determine via endoscopic transplantation of intestinal organoids derived from Kras(G12D), Braf(V637E) and Pik3ca(H1047R) mice into the large intestine of wild-type mice. Importantly, detection of involved inflammatory mediators and immune cell-subtypes will allow us to genetically target them in vivo using novel in-house generated dual-recombinase systems (DRS). In order to investigate the consequences of inflammation on sporadic intestinal tumourigenesis, models with genetically or experimentally induced chronic inflammation will be applied. Conversely, immunodeficient Rag2;Il2rg–/– mice will be used to elucidate if sporadic intestinal carcinogenesis in Kras(G12D), Braf(V637E) and Pik3ca(H1047R) mice is dependent on inflammation and can be abrogated. This study will generate new mechanistic insights into the microenvironment of cancer subtypes, which could provide a basis for the development of new personalised immune therapies. Campo scientifico medical and health sciencesbasic medicineimmunologymedical and health sciencesclinical medicineoncologymedical and health sciencesclinical medicinetransplantation Programma(i) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Argomento(i) MSCA-IF-2016 - Individual Fellowships Invito a presentare proposte H2020-MSCA-IF-2016 Vedi altri progetti per questo bando Meccanismo di finanziamento MSCA-IF-EF-ST - Standard EF Coordinatore KLINIKUM RECHTS DER ISAR DER TECHNISCHEN UNIVERSITAT MUNCHEN Contribution nette de l'UE € 159 460,80 Indirizzo ISMANINGER STRASSE 22 81675 Muenchen Germania Mostra sulla mappa Regione Bayern Oberbayern München, Kreisfreie Stadt Tipo di attività Higher or Secondary Education Establishments Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Partecipazione a programmi di R&I dell'UE Opens in new window Rete di collaborazione HORIZON Opens in new window Costo totale € 159 460,80