Epithelial Calcineurin Promotes Microbiota-Dependent Colorectal Cancer

Intestinal inflammation and activation of inflammation-associated pathways are associated with an increased risk of colorectal cancer. Calcineurin, a phosphatase required for activation of the nuclear factor of activated T cell (NFAT) transcription factors, is linked to inflammation and upregulated in colorectal cancer. Paradoxically, calcineurin inhibition increases tumor formation in vivo, suggesting a role for calcineurin in T cells, whereas inhibition of calcineurin and NFAT inhibits the growth of colorectal cancer cells, suggesting a cell-intrinsic role for calcineurin in colorectal cancers. Peuker, Muff, and colleagues explored the role of calcineurin in intestinal tumor development. In a mouse model of intestinal tumors (Apc^Min/+), intestinal epithelial cell (IEC)–specific deletion of the regulatory B1 subunit of calcineurin (CNB1^ΔIEC) resulted in fewer tumors and reduced tumor size. NFAT inhibition resulted in reduced tumor size and number, decreased cell proliferation, and increased apoptosis, similar to the effects seen in CNB1^ΔIEC mice, suggesting that calcineurin promotes intestinal tumorigenesis through NFAT. Toll-like receptors (TLR) recognize intestinal microbiota, and TLR agonists have been shown to activate calcineurin and NFAT in dendritic cells. TLR4 stimulation similarly activated calcineurin and increased NFAT-dependent transcription in colorectal cancer cells. A TLR agonist increased cell proliferation in a calcineurin- and NFAT-dependent manner, and enhanced the growth of CNB1–wild-type, but not CNB1^ΔIEC, tumors. This tumorigenic effect required the recognition of the microbiota by TLRs, as antibiotic treatment in Apc^Min/+ tumors decreased NFAT-dependent transcription and reduced tumor number and size. Calcineurin regulated tumor development via regulation of the epithelial response to tumor-associated changes in the commensal microbiota and by NFAT-dependent activation of stem cell–associated genes in tumor cells. Consistent with these findings, strong nuclear NFAT staining was observed in human colorectal cancer tumors and associated with reduced survival. Together, these findings highlight a cell-intrinsic pathway in the epithelial tumor cells that receives signals from the microbiota to promote tumor growth.

Peuker K, Muff S, Wang J, Künzel S, Bosse E, Zeissig Y, et al. Epithelial calcineurin controls microbiota-dependent intestinal tumor development. Nat Med 2016 Apr 4 [Epub ahead of print].