Michael Yaffe
Koch Institute for Integrative Cancer Biology, MIT, and Beth Israel Deaconess Medical Center
"Dynamic Re-Wiring of Signaling Networks in the DNA Damage Response - Using Systems Biology to Optimize Combination Therapy for Cancer"
Protein kinases and phosphoserine/threonine-binding domains such as 14-3-3 proteins, FHA domains, Polo-box domains, and BRCT domains form PTM-dependent signaling networks to control growth factor and cytokine responses, cell cycle progression, and the response to DNA damage. How signals from these different signaling pathways are integrated and processed to control cell fate decisions is unclear. To address this, we have been developing systems biology-based models of DNA damage signaling where kinase activities, protein phosphorylation, and phosphoprotein-binding events for multiple signaling pathways are quantitatively measured at densely sampled points in time, along with cellular responses such as cell cycle arrest, cytokine production, autophagy, and apoptosis. The resulting large dataset of signals and responses are then related to each other mathematically using partial least squares regression, principal components analysis, and time-interval stepwise regression. We have used this approach, together with targeted RNAi screens to identify novel signaling pathways and epigenetic modulators of breast, bone, and non-small cell lung cancers to DNA damaging chemotherapy and gamma radiation. The analysis has identified novel targets in the DNA damage response, and new treatment approaches that can therapeutically re-wire signaling pathways within tumor cells to dramatically improve tumor cell killing by conventional clinical DNA damaging treatments.
