Cells in multicellular organisms switch between distinct cell fates, such as proliferation or differentiation into specialized cell types. Genome-wide gene regulatory networks govern this behavior. Theoretical studies of complex networks suggest that they can exhibit ordered (stable) dynamics, raising the possibility that cell fates may represent high-dimensional attractor states. We used gene expression profiling to show that trajectories of neutrophil differentiation converge to a common state from different directions of a 2773-dimensional gene expression state space, providing the first experimental evidence for a high-dimensional stable attractor that represents a distinct cellular phenotype.
Mapping of protein signaling networks within tumors can identify new targets for therapy and provide a means to stratify patients for individualized therapy. Despite advances in combination chemotherapy, the overall survival for childhood rhabdomyosarcoma remains f60%. A critical goal is to identify functionally important protein signaling defects associated with treatment failure for the 40% nonresponder cohort. Here, we show, by phosphoproteomic network analysis of microdissected tumor cells, that interlinked components of the Akt/mammalian target of rapamycin (mTOR) pathway exhibited increased levels of phosphorylation for tumors of patients with short-term survival. Specimens (n = 59) were obtained from the Children's Oncology Group Intergroup Rhabdomyosarcoma Study (IRS) IV, D9502 and D9803, with 12-year follow-up. High phosphorylation levels were associated with poor overall and poor disease-free survival: Akt Ser 473 (overall survival P < 0.001, recurrence-free survival P < 0.0009), 4EBP1 Thr 37/46 (overall survival P < 0.0110, recurrence-free survival P < 0.0106), eIF4G Ser 1108 (overall survival P < 0.0017, recurrence-free survival P < 0.0072), and p70S6 Thr 389 (overall survival P < 0.0085, recurrence-free survival P < 0.0296). Moreover, the findings support an altered interrelationship between the insulin receptor substrate (IRS-1) and Akt/mTOR pathway proteins (P < 0.0027) for tumors from patients with poor survival. The functional significance of this pathway was tested using CCI-779 in a mouse xenograft model. CCI-779 suppressed phosphorylation of mTOR downstream proteins and greatly reduced the growth of two different rhabdomyosarcoma (RD embryonal P = 0.00008; Rh30 alveolar P = 0.0002) cell lines compared with controls. These results suggest that phosphoprotein mapping of the Akt/mTOR pathway should be studied further as a means to select patients to receive mTOR/IRS pathway inhibitors before administration of chemotherapy. [Cancer Res 2007;67(7):3431-40]
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