DSMT16 · Deciphering causes and consequences of inflammation in subtypes of sporadic intestinal cancer

Deciphering causes and consequences of inflammation in subtypes of sporadic intestinal cancer

Colorectal cancer (CRC) is a heterogeneous disease with diverse morphological and molecular subtypes. This heterogeneity is considered as one of the principal obstacles to efficiently treat the disease and to predict patient outcome. Whereas next-generation sequencing efforts revealed the mutational landscape of CRC, little is known on how different oncogenes and mutation patterns in the primary tumour educate their specific microenvironment (composed of immune- and stroma cells as well as microbiota) and dictate the pro- and anti-tumourigenic immune response of the stroma. Hence, the overall objective of this study was to decipher the cellular composition of the tumour microenvironment (TME) and associated inflammatory signals, which may be induced by activation of distinct oncogenes (Kras(G12D), Braf(V637E), Pik3ca(H1047R)) or by inactivation of the tumour suppressor gene Apc. Systematic immunophenotyping of mouse models, which express oncogenic Kras(G12D), Braf(V637E) and Pik3ca(H1047R) or harbour a loss-of function deletion of Apc, using multi-colour microscopy (histocytometry), flow cytometry and transcriptomic profiling, was performed to assess the cellular composition of the TME in molecular subtypes of intestinal cancer and different tumour stages (early lesions and advanced tumour stages). In order to understand how the activation of an oncogene or deletion of a tumour suppressor gene in intestinal epithelial cells (IEC) may influence the TME, it was important to delineate the molecular basis of the tumours. For this purpose, tumour cells from the different mouse models were isolated, 3D organoid (epithelial) cultures were generated and a living organoid biobank of murine intestinal tumours was set up. Since the above-mentioned endogenous models of intestinal subtypes predominantly develop tumours in the small intestine, which is a rare location of human cancers, it was of great importance to study tumour formation also in its native anatomical location (colon). For this purpose, an orthotopic transplantation model that is based on colonoscopy-guided injections of intestinal organoids into the submucosa of the rectum/distal colon was established. Importantly, this model also enabled us to efficiently model CRC subtypes in different syngeneic immuno-competent and immuno-deficient models, to functionally analyse tumour development from initiation to metastasis and to assess the cross-talk of cancer cells with their microenvironment. To conclude this action, our data suggest that the mutational make-up of the tumour dictates its specific immune microenvironment, and also drives microbial alterations in the gut, which in turn may determine tumour development and survival. The results of this study could provide a basis for the development of new personalised cancer immune therapies for CRC.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз