Ricerc@Sapienza

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 chronic inflammation in patients with inflammatory bowel disease (IBD) represents one of the highest risk factors for CRC development. Thus, identification of novel cellular and molecular druggable targets able to restore the physiological balance of pro-inflammatory molecules is a pressing unmet need.

Natural killer (NK) cells and innate lymphoid cells (ILCs) are specialized cytokine producer cells which patrol environmental interfaces to defend against infections and protect barrier integrity. These cells also participate in regulating gut inflammation, playing both protective and pathogenic functions during colitis-associated cancer. However, most of the molecular mechanisms responsible for the promotion of inflammation and cancer remain to be elucidated, yet.

Members of the Signal Transducer and Activator of Transcription (STAT) family are important mediators for signaling events downstream of many cytokine receptors. Due to the relevance of JAK/STAT-signaling in both IBD and CRC, this pathway is an attractive therapeutic target. We have previously described a broad expression of STAT4 in intestinal ILCs expressing natural cytotoxicity triggering receptors (NCRs) and unraveled non-redundant roles of this transcription factor in NK and ILCs. Building upon these findings, we believe that by targeting STAT4 in ILCs we can achieve modulation of the inflammatory microenvironment during intestinal inflammation and cancer.

Overall, this research plan aims i) to establish the impact of the conditional deletion of STAT4 in NCR+ ILCs in the pathogenesis of CRC; ii) to identify STAT4-dependent effector programs in mouse ILCs, relevant for generation of novel strategies for prevention of colitis-induced CRC.