Abstract IA01: Recent advances in studying EGFR and its ligands in colorectal cancer
Authors: Coffey Robert J. 
Published: March 2017

At Vanderbilt, we have fashioned a three-pronged approach to study colorectal cancer (CRC): from in vitro studies to those both in mouse and humans. In vitro, we have analyzed trafficking and cell-surface delivery of EGFR and its ligands in a battery of CRC cell lines that retain the ability to form uniform polarizing monolayers on Transwell filters. In the mouse, we have discovered that the pan-ERBB inhibitor, LRIG1, marks a largely quiescent population of colonic stem cells distinct from LGR5 and that administration of tamoxifen to Lrig1-CreET2;Apcfl/+ mice eliminates one allele of Apc and results in highly penetrant, multiple, histologically advanced adenomas in the distal colon 50-100 days later; these adenomas show the expected loss of the 2nd Apc allele. Later this month, we will submit the 4th renewal of our GI Specialized Programs of Research Excellence (SPORE) that focuses on CRC.

An advance in each of these areas will be discussed. Based on our trafficking studies, we have discovered that EGFR ligands can be released in endosome-derived small vesicles called exosomes. The ligands are signaling competent and bind to EGFR on recipient cells. We have termed this new mode of signaling, Exosomal Targeted Receptor Activation (ExTRAcrine). We have recently advanced this work to studying EGFR in exosomes isolated from mouse and human plasma using a method we have developed, fluorescence-based vesicle sorting (FAVS). Second, a limitation to studying EGFR in the mouse is the lack of robust reagents to monitor EGFR by immunohistochemistry. To circumvent this limitation, we have used CRISPR gene editing to target the endogenous mouse locus to create a chimeric EGFR-Emerald (green) reporter mouse. We will present data showing the value of this mouse in monitoring EGFR in the normal colon and in colonic tumors generated in our Lrig1-CreERT2;Apcfl/+ mouse model. Finally, we have developed a new 3D system to study CRC. Using this system, we have discovered a novel mode of cetuximab resistance and will show its relevance to human CRC.

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Citation Format: Robert J. Coffey. Recent advances in studying EGFR and its ligands in colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr IA01.