Inflamed T cells and stroma drive gut tumors.

Inactivating somatic mutations causing loss of function in the tumor suppressor gene STK11 (serine-threonine kinase 11), which encodes the protein LKB1 (liver kinase B1), frequently occur in several sporadic cancers, notably lung, pancreatic, and female reproductive tumors. Additionally, inherited heterozygous germline mutations in STK11 cause Peutz-Jeghers syndrome (PJS), a cancer predisposition syndrome ( 1 ). A hallmark of PJS is the growth of numerous benign gastrointestinal (GI) hamartomatous polyps and an elevated risk of developing malignancies in several organs ( 2 ). Studies in mouse models of PJS have pointed to LKB1 deficiency in the stroma, not epithelium, as the contributing factor for the formation of the GI polyps ( 3 ). Stroma consists of the fibroblasts, smooth muscle, extracellular matrix, and basement membrane that support epithelial tissue. However, how LKB1 deficiency in stromal cells could trigger polyp formation was unclear. Two recent studies now shed light on the mechanism of PJS polyp formation. On page 406 of this issue, Poffenberger et al. ( 4 ) find that loss of a single allele of Stk11 in T cells is sufficient to drive the formation of GI polyps. Similarly, a study by Ollila et al. ( 5 ) demonstrated that heterozygous loss of Stk11 in gastric stromal cells was sufficient to drive GI polyp formation. Transcriptional profiling in both studies revealed an up-regulation of inflammatory cytokines involved in promoting the expansion and overgrowth of both stroma and normal GI epithelium. By finding that inflammation in the stromal compartment due to LKB1 loss in T cells ( 4 ) or stromal cells ( 5 ) drives polyp formation, these studies highlight how inflammatory signals can profoundly alter the microenvironment and fuel tumor formation.