Loss of DRO1/CCDC80 in the tumor microenvironment promotes carcinogenesis

Tumors are composed of the tumor cells and the surrounding microenvironment. Both are closely interwoven and interact by a complex and multifaceted cross-talk which plays an integral part in tumor initiation, growth, and progression. has been shown to be a potent suppressor of colorectal cancer and ubiquitous inactivation of strongly promoted colorectal carcinogenesis in mice and in a chemically-induced colorectal cancer model. The aim of the present study was to investigate whether 's tumor suppressive function is tumor-cell-autonomous. Expression of in cancer cells had no effect on both colon tumor development in mice and formation of xenograft tumors. In contrast, DRO1/CCDC80 loss in the microenvironment strongly increased tumor growth in xenograft models, inhibited cancer cell apoptosis, and promoted intestinal epithelial cell migration. Moreover, stromal inactivation facilitated formation of intestinal epithelial organoids. Expression analyses showed to be significantly down-regulated in murine gastric cancer associated fibroblasts, in colon tumor primary stromal cells and in microdissected stroma from human colorectal cancer compared to normal, non-tumor stroma. Our results demonstrate epithelial derived DRO1/CCDC80 to be dispensable for intestinal tissue homeostasis and identify Dro1/Ccdc80 as tumor suppressor in the tumor microenvironment.