Targeting STAT3 Signaling in COL1+Fibroblasts Controls Colitis-Associated Cancer in Mice

Simple Summary Colitis-associated cancer is a colorectal cancer entity with poor prognosis and limited therapeutic options typically occurring as long-term complications of inflammatory bowel diseases. Connective tissue cells such as cancer-associated fibroblasts are part of the tumor microenvironment that can influence cancer development. The aim of this study was to determine the role of STAT3 activation in a frequent subset of fibroblasts during the development of inflammation-associated colorectal cancer in vivo. Our work highlights the functional role of cancer-associated fibroblasts in colitis-associated cancer, suggesting that strategies targeting the activation of that cell type could evolve as promising therapeutic option in inflammation-associated colorectal cancer and possibly additional entities. Colorectal cancer (CRC) is a common disease and has limited treatment options. The importance of cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME) in CRC has been increasingly recognized. However, the role of CAF subsets in CRC is hardly understood and opposing functions of type I (COL1+) vs. type VI (COL6+) collagen-expressing subsets were reported before with respect to NF kappa B-related signaling. Here, we have focused on COL1+ fibroblasts, which represent a frequent CAF population in CRC and studied their role upon STAT3 activation in vivo. Using a dual strategy with a conditional gain-of-function and a conditional loss-of-function approach in an in vivo model of colitis-associated cancer, tumor development was evaluated by different readouts, including advanced imaging methodologies, e.g., light sheet microscopy and CT-scan. Our data demonstrate that the inhibition of STAT3 activation in COL1+ fibroblasts reduces tumor burden, whereas the constitutive activation of STAT3 promotes the development of inflammation-driven CRC. In addition, our work characterizes the co-expression and distribution of type I and type VI collagen by CAFs in inflammation-associated colorectal cancer using reporter mice. This work indicates a critical contribution of STAT3 signaling in COL1+ CAFs, suggesting that the blockade of STAT3 activation in type I collagen-expressing fibroblasts could serve as promising therapeutic targets in colitis-associated CRC. In combination with previous work by others and us, our current findings highlight the context-dependent roles of COL1+ CAFs and COL6+ CAFs that might be variable according to the specific pathway activated.