(202d) Metabolic Reprogramming in Tumor Cells Is Modulated by Integrin Binding | AIChE

(202d) Metabolic Reprogramming in Tumor Cells Is Modulated by Integrin Binding


Murphy, T. A. - Presenter, Vanderbilt University
Liu, S. - Presenter, Vanderbilt University
Hassanein, M. - Presenter, Vanderbilt University
Quaranta, V. - Presenter, Vanderbilt University

The key to fighting cancer is to discover and exploit physiological differences between diseased and normal cells. These differences allow clinicians to detect and selectively kill cancerous cells against a large background of non-cancerous tissues. Past approaches have focused mainly on molecular targets that control DNA replication or mitogen signaling in tumor cells and have overlooked the unique metabolic aspects of tumor growth. However, researchers have long understood that malignant cells display highly abnormal metabolic tendencies owing to the increased nutritional demands of their rapid proliferation. In fact, one of the first cancer phenotypes to be systematically described (over 85 years ago) is the so-called Warburg effect whereby cancer cells exhibit increased flux of glucose to lactate under aerobic conditions.

Recent data from the Quaranta lab suggest that tumor metabolism is constrained by a particular extracellular matrix protein, namely laminin-5 (Ln-5). This work reveals that shRNA knockdown of Ln-5 or inhibition of its integrin receptor results in dramatically increased growth of tumor xenografts. These Ln-5 knockdown cells also exhibit a pronounced shift toward aerobic glycolysis when grown in vitro, with glucose uptake increasing nearly 8-fold. This is the first time, to our knowledge, that changes in integrin binding have been shown to regulate the Warburg effect. We are conducting metabolic flux analysis (MFA) studies using 13C-labeled glucose tracers and GC-MS profiling to further investigate the global metabolic adaptations that occur in the absence of Ln-5. We hypothesize that disruption of normal integrin signaling triggers cell-wide metabolic reprogramming, and that these changes are key contributors to the unregulated growth and apoptotic resistance exhibited by tumor cells.