Understanding the role of mast cells in colorectal cancer progression

Background: Mast cells (MCs) are granulated immune cells mainly known for their involvement in IgE-mediated allergic disorder. More recent evidence supports a role of MCs in the transition from chronic inflammation to transformation. However, MCs contribution to tumorigenesis is still controversial. Our previous results showed accumulation of activated MCs in a murine model of colitis-induced colorectal cancer (CRC). Purpose: The aim of this study is to investigate the role of MCs during CRC progression by employing MC-deficient murine models. Results: We have initially used the murine model of colitis-induced CRC (AOM/DSS) before and after intraperitoneal injection of anti-mouse c-Kit antibody that is known to deplete MCs. Compared with untreated mice, antibody-treated mice showed a significant reduction in the abundance of MCs accompanied by inhibition of tumor burden. We are also generating a c-Kit-independent constitutive mouse model of MC deficiency (“Hello Kitty” Cpa3-Cre; Mcl-1fl/fl mice). These mice will be treated with AOM/DSS and the kinetics and incidence of CRC development will be established. Cytokines, chemokines, and growth factors present in tumor microenvironment (TME) will be analysed by multiplex Luminex assays. Moreover, the composition of immune infiltrate in TME will be analysed by single-cell RNA-seq in the presence and absence of MCs. Conclusions: Our previous data support a role for MCs in favouring tumor progression. However, c-Kit is also expressed on colonic tumors and its neutralization can be directly responsible for the observed inhibition of tumor growth. Thus, MCs exact role in CRC development will be clarified by the “Hello Kitty” model.