A Systems Biology Approach to Modeling Signaling Crosstalk in Cell Fate Decisions
Ildefonso, Geena Victoria
A central challenge in biomedical research is to understand how cells process information, respond to perturbations, and make decisions. Cells are constantly processing extracellular stimuli that can lead to multiple phenotypic outcomes. The molecular mechanisms that control signal processing in cells remain poorly understood due to the high complexity of the underlying biochemical interaction networks. In this work, we take a systems biology approach to understand cellular decisions in two signal transduction pathways. We focus on (i) Characterizing the molecular mechanisms that underly necroptosis execution, a type of programmed cell death, using a Bottom-up approach, and (ii) The role of Notch signaling and Small cell lung cancer (SCLC) using a Top-down approach. Using a Bottom-up approach, we developed the first biochemical model of necroptosis derived from published literature incorporating known biology, fit to experimental data, and reveal a dynamical systems analysis identified four distinct modes of necroptosis signal execution, which can be distinguished based on rate constant values and the roles of the deubiquitinating enzymes A20 and CYLD in the regulation of RIP1 ubiquitination. We also performed sensitivity analyses of initial protein concentrations and rate constants and identified potential targets for modulating necroptosis sensitivity among the biochemical events involved in RIP1 ubiquitination regulation and the decision between complex II degradation and necrosome formation. Using a Top-down approach, we explore the combinatorial complexity between the four Notch ligands, and four Notch receptors across the five known SCLC subtypes and examine the expression profiles of downstream signaling and Notch inhibitor activation. We find that the Notch ligands and receptors are differentially expressed across all SCLC subtypes, hypothesized to be due to the upregulation of four inhibitors (DLL3, LSD1, PHB2, and HES6) to Notch signaling. In conclusion, the research presented herein has provided new insights to understanding some of the many facets that contribute to cell fate decisions, specifically focused on elucidating mechanisms involved in necroptosis, and how notch signaling is involved in SCLC.