The long-term goal of my laboratory is to elucidate the role of transforming growth factor-alpha (TGFalpha) and related peptides in epithelial cell biology with a particular focus on the neoplastic consequences of their dysregulation. TGFalpha is a member of a family of peptides that bind the EGF receptor (EGFR); these include EGFR); these include EGF, amphiregulin (AR), heparin-binding EGF-like growth factor (HB- EGF) and betacellulin (BTC). During the previous granting period, we have established valuable in vitro (polarized epithelial cells) and in vivo (transgenic and null mice) models to examine the actions of these growth factors. We have demonstrated that TGFalpha is delivered preferentially to the basolateral compartment of polarized epithelial cells; EGFR is restricted to this compartment and thus TGFalpha acts in an autocrine manner. In contrast, EGF has been immunolocalized to the apical compartment by laser scanning confocal microscopy (LSCM). Thus EGF could not act in an autocrine manner in this system since tight junctions prevent access of this apically sorted EGF to basolateral EGFRs in intact monolayers. We submit that the study of the action of growth factors in polarized epithelial cells offers a significant in vitro advance in that it stimulates the in vivo context in which there is spatial compartmentalization of ligands and receptors. The study of mouse models that we have developed (MMTV-TGFalpha transgenic mice and EGFR null mice) has provided important insights into the mechanisms of action of TGFalpha and the EGFR in vivo. Experiments are proposed to define the mechanism underlying basolateral sorting of TGFalpha and to examine the trafficking of EGF, AR, HB-EGF and BTC in polarized epithelial cells. Mechanistic studies of EGFR-regulated release of prostaglandins into the basolateral compartment of polarized colorectal cancer cell lines represent a novel line of investigation with important clinical implications. The biological consequences (mitogenicity, apoptosis) of cross-induction of TGFalpha family members will be examined in nontransformed rat intestinal epithelial cells. These in vitro studies will be complemented by generating mice with a targeted disruption of AR and crossing homozygous AR-deficient progeny to TGFalpha deficient mice, as well as by pursuing further studies of EGFR null mice.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Vanderbilt University Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Herring, Charles A; Banerjee, Amrita; McKinley, Eliot T et al. (2018) Unsupervised Trajectory Analysis of Single-Cell RNA-Seq and Imaging Data Reveals Alternative Tuft Cell Origins in the Gut. Cell Syst 6:37-51.e9
Schulte, Michael L; Fu, Allie; Zhao, Ping et al. (2018) Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models. Nat Med 24:194-202
Banerjee, Amrita; McKinley, Eliot T; von Moltke, Jakob et al. (2018) Interpreting heterogeneity in intestinal tuft cell structure and function. J Clin Invest 128:1711-1719
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
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
Starchenko, Alina; Graves-Deal, Ramona; Yang, Yu-Ping et al. (2017) Clustering of integrin ?5 at the lateral membrane restores epithelial polarity in invasive colorectal cancer cells. Mol Biol Cell 28:1288-1300
Lu, Yuanyuan; Zhao, Xiaodi; Liu, Qi et al. (2017) lncRNA MIR100HG-derived miR-100 and miR-125b mediate cetuximab resistance via Wnt/?-catenin signaling. Nat Med 23:1331-1341
Short, Sarah P; Kondo, Jumpei; Smalley-Freed, Whitney G et al. (2017) p120-Catenin is an obligate haploinsufficient tumor suppressor in intestinal neoplasia. J Clin Invest 127:4462-4476
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

Showing the most recent 10 out of 176 publications