Abstract PR2: A systems biology approach to elucidating the consequences of complex ternary interactions of heparin, FGF ligands, and FGF receptor on downstream signaling in NSCLC cells

Autocrine/paracrine FGF signaling has been implicated in non-small cell lung cancer (NSCLC) development and progression. In multiple NSCLC cell lines, a switch from FGFR2-IIIb expressed in lung epithelial cells to FGFR1-IIIc and FGFR2-IIIc, results in autocrine response to FGF2 and FGF9 ligands also expressed by these cell lines. FGF2 and FGFR1 expression have also been detected in patient samples and shown to correlate with short survival times. The FGF signaling complex involves a ternary interaction of FGF ligand, receptor, and heparin sulfate glycosaminoglycans (HSGAGs). HSGAGs bind directly to both ligand and receptor, and can serve both to stabilize the receptor-ligand complex and to sequester autocrine/paracrine ligands, increasing local concentrations. A systems approach combining experiment and modeling was used to understand the complex interplay of these components and their implications on cell signaling and behavior. We focused on the signaling behavior of NSCLC cell line NCI-H1703, which predominantly expressed FGFR1. We interrogated pathway dynamics with both FGF2 and FGF9 ligands and found varying Erk1/2 activation kinetics. Using a model encompassing the ternary complex formation in the cellular membrane, ligand-mediated receptor dimerization and phosphorylation, and subsequent kinase cascade to activate Erk1/2, we were able to identify potential mechanisms driving these differences. Additional perturbations of extracellular interactions and intracellular signaling were able to support these hypotheses. These results highlight the role of the extracellular interactions between ligand, receptor, and HSGAGs in controlling downstream behavior. This proffered talk is also presented as Poster A5. Citation Format: Diana H. Chai, Jaeyeon Kim, Jannik Vollmer, Andrijana Radivojevic, Jitendra Kanodia, Marco Muda, Birgit Schoeberl. A systems biology approach to elucidating the consequences of complex ternary interactions of heparin, FGF ligands, and FGF receptor on downstream signaling in NSCLC cells [abstract]. In: Proceedings of the AACR Special Conference on Chemical Systems Biology: Assembling and Interrogating Computational Models of the Cancer Cell by Chemical Perturbations; 2012 Jun 27-30; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2012;72(13 Suppl):Abstract nr PR2.