Abstract 1624: Lrig1 is an Egfr-dependent tumor suppressor in mouse duodenal and colonic neoplasia

Abstract

Abstract Leucine-rich repeats and immunoglobulin-like domain 1 (Lrig1) is a pan-ErbB negative regulator. Lrig1 null mice develop spontaneous duodenal adenomas by 3-4 months of age but they exhibit no overt colonic pathology (AE Powell Cell 149:146-158, 2012). To examine a possible tumor suppressor role for Lrig1 in colonic neoplasia, we utilized Lrig1CreERT2 and Lrig1Apple mice in which a tamoxifen-inducible Cre recombinase or an Apple fluorescent reporter were inserted into the translational start site of endogenous Lrig1, thus creating Lrig1 null mice. Colonic tumors were generated by administration of AOM/DSS to Lrig1CreERT2/CreERT2 mice and by administration of tamoxifen (TAM) to Lrig1CreERT2/Apple;Apcflox/+ mice to induce loss of one Apc allele. Compared to littermate control mice, there was a significant increase in colonic tumor number in both Lrig1 null cohorts (p=0.016 and p=0.007, respectively). We previously reported Egfr was the most upregulated ErbB family member in Lrig1 null duodenal tumors (Y Wang Am J Path 185:1123-1134, 2015). To directly implicate Egfr in both Lrig1 null duodenal and colonic tumors, we administered TAM at 6 weeks of age to Lrig1CreERT2/CreERT2;Egfrflox/flox mice. At 6 months of age, all oil-injected mice developed tumors, whereas tumors were not detected in 8/21 (38.1%) of TAM-injected mice; the tumor volume in TAM-injected mice was reduced to 7.78 mm3 (73.5%) compared to (10.58 mm3) in the oil-injected group as measured by MRI scanning (p<0.05). In the AOM/DSS colonic tumor model, administration of TAM at 6 weeks of age to Lrig1CreERT2/CreERT2;Egfrflox/flox mice resulted in a significant decrease in tumor number (p=0.021) but not size compared to oil-injected mice. These results indicate that Lrig1 is an Egfr-dependent tumor suppressor in both mouse duodenal and colonic neoplasia. Citation Format: Robert J. Coffey, Hiro Niitsu, Yuanyuan Lu, Won Jae Huh, Jeffrey L. Franklin. Lrig1 is an Egfr-dependent tumor suppressor in mouse duodenal and colonic neoplasia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1624.