Department of Molecular Medicine
Contact Information: Email: email@example.com; Phone: 607-253-3888
Grant Number: 3 R01 GM040654-23S1
Title: Characterization of Growth Factor-Coupled Signaling: Administrative Supplement for Collaborative Science
Annual Direct Cost: $90,000
Project Period: 09/01/2011-8/31/2014
DESCRIPTION: (provided by applicant): Studies in the Cerione laboratory supported by GM040654 have led to the discovery of two signaling pathways that play important roles in cell growth regulation. One involves EGFR signaling through the small GTPase Cdc42 to regulate EGFR degradation, while the second links heregulin/ErbB2 signaling to the RNA-processing machinery. Additionally, the Cerione laboratory discovered a novel connection between EGFR/Cdc42-signaling and the activation of a metabolic enzyme, glutaminase (GLS1), which leads to the elevations in glutamine metabolism required by rapidly proliferating cells and transformed/cancer cells. Recent findings by Cerione’s group show that an important part of the metabolic changes occurring in breast cancer cells is to generate and shed microvesicles that endow normal cells with transformed characteristics. However, we feel that it is now imperative to test these interesting findings in more stringent cancer models and in vivo systems. Thus, supplemental funding to GM040654 is being requested to pursue a collaborative effort between the Cerione laboratory and Dr. Natasza Kurpios, a junior faculty member here at Cornell who has a great deal of experience in developing in vivo models to study development and cancer. These collaborative efforts will take advantage of Dr. Kurpios’ expertise and the availability of recently generated mice in which Cdc42 has been conditionally deleted from the mammary gland, to address three important experimental aims. The first will be to examine the potential interplay between breast cancer cell lines and primary mammary epithelial cells, by assessing the abilities of breast cancer cells to induce the transformation of primary epithelial cells obtained from Cdc42 conditional knock-out mice versus control littermates. The second will examine the interplay between breast cancer cell lines and either wild-type versus Cdc42-null primary mammary epithelial cells in generating mammary tumors following transplantation into the cleared fat pads of mice. We are extremely interested in seeing whether the presence of Cdc42 in recipient mammary epithelial cells is essential for microvesicle-induced transformation and tumor formation in vivo. The third experimental aim is to examine the effectiveness of an exciting small molecule inhibitor of Cdc42-dependent metabolic changes for its effectiveness in blocking transformation and tumor formation in these model systems. These three lines of studies, which are only possible through collaborative efforts, will greatly contribute toward establishing that those signaling activities identified in biochemical studies supported by GM040654 are genuinely relevant to cancer progression as well as set the stage for exciting future collaborations between the Cerione and Kurpios laboratories.
PUBLIC HEALTH RELEVANCE: EGF receptor (EGFR) family members have been implicated in a number of human cancers. Thus far, we have used biochemical, structural biology, and cell biology-based approaches, to identify signaling pathways downstream from EGFR family members that regulate EGFR degradation and activate a metabolic enzyme that helps satisfy the bio-energetic needs of highly proliferating cells and cancer cells. We now want to confirm these findings using in vivo model systems for mammary cancer. These efforts should put us in better position to identify new therapeutic strategies for blocking cancer progression.