LAT1 expression influences Paneth cell number and tumor development in ApcMin/+ mice

BackgroundAmino acid transporters play an important role in supplying nutrition to cells and are associated with cell proliferation. L-type amino acid transporter 1 (LAT1) is highly expressed in many types of cancers and promotes tumor growth; however, how LAT1 affects tumor development is not fully understood.MethodsTo investigate the role of LAT1 in intestinal tumorigenesis, mice carrying LAT1 floxed alleles that also expressed Cre recombinase from the promoter of gene encoding Villin were crossed to an Apc(Min/+) background (LAT1(fl/fl); vil-cre; Apc(Min/+)), which were subject to analysis; organoids derived from those mice were also analyzed.ResultsThis study showed that LAT1 was constitutively expressed in normal crypt base cells, and its conditional deletion in the intestinal epithelium resulted in fewer Paneth cells. LAT1 deletion reduced tumor size and number in the small intestine of Apc(Min/+) mice. Organoids derived from LAT1-deleted Apc(Min/+) intestinal crypts displayed fewer spherical organoids with reduced Wnt/beta-catenin target gene expression, suggesting a low tumor-initiation capacity. Wnt3 expression was decreased in the absence of LAT1 in the intestinal epithelium, suggesting that loss of Paneth cells due to LAT1 deficiency reduced the risk of tumor initiation by decreasing Wnt3 production.ConclusionsLAT1 affects intestinal tumor development in a cell-extrinsic manner through reduced Wnt3 expression in Paneth cells. Our findings may partly explain how nutrient availability can affect the risk of tumor development in the intestines.

Automated summary

This study found that L-type amino acid transporter 1 (LAT1) is expressed constitutively in normal cells and plays an important role in tumor development and progression. The conditional deletion of LAT1 was shown to reduce the size and number of intestinal tumors and affect tumor initiation by reducing Wnt3 expression in Paneth cells. These findings partly explain how nutrient availability can influence the development of intestinal tumors.