CORNET

deCiphering the rOle of micRoenvironment after low-dose exposure for coloN carcinogenEsis and radiaTion risk

Project objectives and goals

The risk of developing colon cancer (CC) has been associated with medical and environmental exposures to ionizing radiation (IR), as seen within the A-bomb survivor cohorts. While a mutational component of sporadic CC development has been extensively studied, less is known about the role of non-mutational processes, such as alterations in tissue microenvironment (TME). Whether low dose radiation (LDR) can induce changes in TME contributing to CC remains unknown. We hypothesize that LDR can alter secretion and the cargo of extracellular vesicles (EVs) produced by colonic epithelial and tissue-resident immune cells leading to the establishment of a pro-tumorigenic and immunosuppressive milieu driving promotion and progression of CC. Macrophages and tumor-initiating epithelial cells are the key players in this process. To test this hypothesis we will utilize an innovative systemic approach consisting of in vivo, in vitro and in silico studies. We will use the inducible KPC:APC mouse model of human CC which allows the study of CC in the intact immune system context. The mice will be exposed to sham, 25 or 250 mGy of X-rays and carcinogenesis will be assessed by histological analyses. Concurrently, we will characterise secreted EVs, their proteome and miRNAs. TME will further be characterized by immunohistology and spatial transcriptomics. The level of oxidative stress will be assessed. We will also generate colon organoids from the KPC:APC mouse to conduct mechanistic studies to understand the precise role of EVs in the communication between different cell types and how LDR affects those to promote neoplastic transformation. This will also be achieved by experimenting with co-cultured cells, isolated and/or manipulated EVs. Key findings will be validated in human-derived colon organoids and CC tumoroids to assess the transfer of knowledge to humans. Our in silico study will utilize a Systems Biology approach to carry out multimodal and multiomics data integration to refine mechanistic results. The last and the key part of the study will use Biologically-Based Risk Modeling to integrate existing knowledge on the association of LDR and colon cancer from human epidemiological studies with mechanistic knowledge and experimental results providing an ultimate validation of our results for human CC risk assessment following LDR exposures.

 

Project coordinator

Siamak Haghdoost, University of Caen Normandy, ABTE laboratory, AE4651, France