This application is a renewal of a previous R01 Cell-of-Origin Effects on Development of Colon Cancer. During this granting period, we discovered 1) the pan-ErbB inhibitor, Lrig1, marks largely quiescent colonic epithelial stem cells that are distinct from Lgr5 and 2) Lrig1 acts as a tumor suppressor in vivo. We found that tamoxifen- induced loss of one Apc allele in Lrig1CreERT2;Apcfl/+ mice results in multiple, highly dysplastic colonic adenomas that exhibit stochastic loss of the 2nd Apc allele. An identical approach in Lgr5 driver mice results in no tumors. We have shown that the Lrig1-driven tumors are more histologically advanced than ApcMin colonic tumors, and present preliminary data that the Lrig1-driven tumors exhibit an RNASeq profile similar to that of human colorectal cancer. These findings have led us to focus on Lrig1-related tumors in this retitled application, Roles for Lrig1 in Intestinal Neoplasia. Based on the importance of Egfr in mediating the highly penetrant duodenal tumor phenotype observed in Lrig1-null mice and the marked upregulation of Egfr ligands in colonic tumors of Lrig1CreERT2;Apcfl/+ mice, we have made a new Egfr reporter mouse (EgfrEmGFP) to monitor the Lrig1/Egfr relationship. We also have generated an antibody to mouse Lrig1 that recognizes non-glycosylated Lrig1 that stains long-lived, lineage-labeled, quiescent Lrig1 stem cells and staining is increased in Lrig1 stem cell-driven intestinal tumors. For the first time, we have access to an Egfr antibody that effectively blocks mouse Egfr. This will allow us to examine the mechanism by which Egfr promotes the establishment of colonic neoplasia, as well as to determine the therapeutic efficacy of Egfr blockade in treating established tumors. Given the increasing biological importance of Lrig1, we also propose experiments to examine selected aspects of the regulation and function of LRIG1. Initially, we will determine basolateral sorting elements in the cytoplasmic tail of LRIG1 and the impact of glycosylation on LRIG1 function. At the outset, we will examine these events in the context of EGFR activity, but, as the grant proceeds, we will be alert to additional non-EGFR effects of LRIG1.

Public Health Relevance

Colorectal cancer is a major public health problem, and EGF receptor has been identified as a major therapeutic target. Using novel mouse models generated in our lab, we propose studies to identify and treat colon cancer stem cells that are marked by Lrig1, a negative regulator of the EGF receptor.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA151566-06
Application #
9105576
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Salnikow, Konstantin
Project Start
2010-07-01
Project End
2021-04-30
Budget Start
2016-05-10
Budget End
2017-04-30
Support Year
6
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232
Choi, Eunyoung; Lantz, Tyler L; Vlacich, Gregory et al. (2018) Lrig1+ gastric isthmal progenitor cells restore normal gastric lineage cells during damage recovery in adult mouse stomach. Gut 67:1595-1605
McKinley, Eliot T; Sui, Yunxia; Al-Kofahi, Yousef et al. (2017) Optimized multiplex immunofluorescence single-cell analysis reveals tuft cell heterogeneity. JCI Insight 2:
Yang, Yu-Ping; Ma, Haiting; Starchenko, Alina et al. (2017) A Chimeric Egfr Protein Reporter Mouse Reveals Egfr Localization and Trafficking In Vivo. Cell Rep 19:1257-1267
Wang, Jing; Mouradov, Dmitri; Wang, Xiaojing et al. (2017) Colorectal Cancer Cell Line Proteomes Are Representative of Primary Tumors and Predict Drug Sensitivity. Gastroenterology 153:1082-1095
Li, Cunxi; Singh, Bhuminder; Graves-Deal, Ramona et al. (2017) Three-dimensional culture system identifies a new mode of cetuximab resistance and disease-relevant genes in colorectal cancer. Proc Natl Acad Sci U S A 114:E2852-E2861
Huh, Won Jae; Coffey, Robert J; Washington, Mary Kay (2016) Ménétrier's Disease: Its Mimickers and Pathogenesis. J Pathol Transl Med 50:10-6
Yu, Huapeng H; Dohn, Michael R; Markham, Nicholas O et al. (2016) p120-catenin controls contractility along the vertical axis of epithelial lateral membranes. J Cell Sci 129:80-94
Simmons, Alan J; Scurrah, Cherié R; McKinley, Eliot T et al. (2016) Impaired coordination between signaling pathways is revealed in human colorectal cancer using single-cell mass cytometry of archival tissue blocks. Sci Signal 9:rs11
Gonzalez, Raul S; Cates, Justin M M; Washington, Mary Kay et al. (2016) Adenoma-like adenocarcinoma: a subtype of colorectal carcinoma with good prognosis, deceptive appearance on biopsy and frequent KRAS mutation. Histopathology 68:183-90
Singh, Bhuminder; Carpenter, Graham; Coffey, Robert J (2016) EGF receptor ligands: recent advances. F1000Res 5:

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