IFN/STAT signaling controls tumorigenesis and the drug response in colorectal cancer

: Colorectal cancer (CRC) is caused by genetic alterations, and comprehensive sequence analyses have revealed the mutation landscapes. In addition to somatic changes, genetic variations are considered important factors contributing to tumor development; however, our knowledge on this subject is limited. Familial adenomatous polyposis coli (FAP) is an autosomal-dominant inherited disease caused by germline mutations in the adenomatous polyposis coli (APC) gene. FAP patients are classified into two major groups based on clinical manifestations: classical FAP (CFAP) and attenuated FAP (AFAP). In this study, we established 42 organoids from three CFAP patients and two AFAP patients. Comprehensive gene expression analysis demonstrated a close association between IFN/STAT signaling and the phenotypic features of FAP patients. Genetic disruption of Stat1 in the mouse model of FAP reduced tumor formation, demonstrating that the IFN/STAT pathway is causally associated with the tumor-forming potential of APC-deficient tumors. Mechanistically, STAT1 is downstream target of KRAS and is phosphorylated by its activating mutations. We found that enhanced IFN/STAT signaling in CFAP conferred resistance to MEK inhibitors. These findings reveal the crosstalk between RAS signaling and IFN/STAT signaling, which contributes to the tumor-forming potential and drug response. These results offer a rationale for targeting of IFN/STAT signaling and for the stratification of CRC patients.