Colorectal cancer (CRC) is the second most common cancer in women and third in men, and, overall, the fourth cause of tumor death world-wide. The etiology of CRC is heterogeneous depending on both genetic and environmental factors, including intestinal bowel disease (IBD). Innate lymphoid cells (ILCs) are critical regulators of the intestinal homeostasis, and provide protection from pathogens by quickly triggering inflammation. Moreover, recent findings link the function of ILCs with the progression or clearance of CRC.
Given the importance of innate lymphoid cells (ILCs) in the regulation of intestinal functions, I hypothesized that targeting pro-inflammatory modules in NCR+ ILCs will limit inflammation and tumor formation, in colitis-induced CRC.
The research program I propose will employ a broad approach combining different mouse models of acute colitis and CRC, with cutting-edge next-generation sequencing technologies. Moreover, established and novel mouse models targeting Stat4 in the innate compartment and NCR+ ILCs will be employed to identify the role of this transcription factor in regulation of colon inflammation.
My research plan aims at 1) evaluating the effect of the selective Stat4 deletion in NCR+ ILCs during CRC pathogenesis using established and novel mouse strains; and 2) study the contribution of cell proliferation to the accumulation of NK cells in the inflamed tissues and tumors.
Building upon our unpublished data, I expect that targeting the STAT4-dependent inflammatory modules in NCR+ ILCs will impact the effector programs limiting inflammation and tumor formation, in colitis-induced CRC. This study will provide novel insights into pathways involved in CRC pathogenesis. Moreover, a better understanding of the mechanisms underlying regulation of intestinal NK cell and ILC functions, in settings of inflammation and cancer, will provide the framework to design novel preventive and therapeutic strategies against CRC development and progression.
Colorectal cancer is a global threat, with more than 1 million of new cases and more than 700.000 deaths each year. Although progress has been made to understand the pathogenesis of this disease, the molecular and cellular mechanisms responsible for the development of CRC have not been fully elucidated. The chronic inflammation associated with IBD is a risk factor, and, at the same time, the features of the immune cells infiltrating the tumor represent an important prognostic factor for CRC patients. In this context, our aim is to identify novel cellular and molecular pathways involved in regulation of the inflammatory response before and after development of cancer. Due to the relevance of STAT-signaling in both IBD and CRC and the landmark feature of ILCs to produce a vast repertoire of cytokines, and in a large quantity, we propose that understanding how STAT4 regulates ILC functions in the context of chronic inflammation and cancer will provide new paths to design both preventive and therapeutic strategy for CRC. Thus, understanding the role of ILCs and the molecular pathways associated with CRC has profound implications in the Public Health at several levels. At first, correlations between ILC phenotype/functions and cancer progression will improve the prognostic power of the Immunoscore, recently proposed for CRC. Moreover, the transcriptomic data we plan to generate in this proposal will have the potential to reveal new biological pathways and new players involved in the pathogenesis of CRC. Targeting these molecules by using available drugs or by synthesis of new small molecules will pave the way for novel therapeutic strategies. Finally, this proposal has a huge impact also for IBD patients. Indeed, we will identify proinflammatory modules which will be targeted for the preventive treatment of colitis-associated CRC. Finally, mouse models of colitis have revealed both unique and redundant roles for ILCs, while their role in cancer is still poorly investigated. How these cells contribute in IBD and CRC in humans is still under debate and it represents a hot topic in the field of immunology. Despite the possible redundant functions in human, it is undoubtedly clear that ILCs are potent and rapid cytokine producers. Here we propose that a better understanding on how ILC responses are regulated will provide a useful tool for the treatment of these diseases. Moreover, the Immunoscore proposed for CRC is currently based only on T cells, integration of the ILC features in this score has the potential to improve its prognostic value.