Abstract
Loss of intestinal Lrig1 expression leads to highly penetrant duodenal adenomas.
Major finding: Loss of intestinal Lrig1 expression leads to highly penetrant duodenal adenomas.
Mechanism: LRIG1 negatively regulates ERBB signaling to maintain intestinal stem cell homeostasis.
Impact: The mutation and downregulation of LRIG1 observed in human cancers may drive tumorigenesis.
Intestinal stem cell homeostasis is critical for maintaining the continuously self-renewing intestinal epithelia while suppressing neoplastic growth. Through lineage tracing in the small intestine and colon of mice, Powell and colleagues identified a population of intestinal stem cells marked by expression of leucine-rich repeats and immunoglobulin-like domains 1 (Lrig1), which encodes a negative regulator of ERBB family receptor tyrosine kinases. LRIG1-positive intestinal stem cells were distinct from the previously characterized, highly proliferative leucine-rich repeat containing G protein-coupled receptor 5 (LGR5)–positive stem cell population, with a low proliferative index and a gene expression profile enriched for cell-cycle inhibitors and other markers of quiescence. To determine whether LRIG1-expressing cells could initiate tumor growth, the authors conditionally deleted one allele of adenomatous polyposis coli (Apc), a tumor suppressor gene that is commonly inactivated in colorectal cancer, in LRIG1-expressing cells of the small-intestinal and colonic epithelia. Upon Apc deletion, 100% of the mice developed intestinal tumors in sites from the duodenum to the distal colon; as expected, the second Apc allele was lost in the tumors. LRIG1 itself was also implicated in tumor suppression, as deletion of Lrig1 from birth resulted in a significant increase in ERBB1-3 protein levels and ERK phosphorylation in the intestinal crypt epithelia. In addition, duodenal adenomas developed in 88% of mice by the age of 5 to 6 months. As cancer genome sequencing efforts have identified mutations in LRIG1 in subsets of human colorectal cancer and glioblastomas, these findings suggest that deregulated stem cell homeostasis and derepression of ERBB signaling due to LRIG1 inactivation may be a driving event in human cancers.
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