Cancer systems biology: a network modeling perspective

Cancer is now appreciated as not only a highly heterogenous pathology with respect to cell type and tissue origin but also as a disease involving dysregulation of multiple pathways governing fundamental cell processes such as death, proliferation, differentiation and migration. Thus, the activities of molecular networks that execute metabolic or cytoskeletal processes, or regulate these by signal transduction, are altered in a complex manner by diverse genetic mutations in concert with the environmental context. A major challenge therefore is how to develop actionable understanding of this multivariate dysregulation, with respect both to how it arises from diverse genetic mutations and to how it may be ameliorated by prospective treatments. While high-throughput experimental platform technologies ranging from genomic sequencing to transcriptomic, proteomic and metabolomic profiling are now commonly used for molecular-level characterization of tumor cells and surrounding tissues, the resulting data sets defy straightforward intuitive interpretation with respect to potential therapeutic targets or the effects of perturbation. In this review article, we will discuss how significant advances can be obtained by applying computational modeling approaches to elucidate the pathways most critically involved in tumor formation and progression, impact of particular mutations on pathway operation, consequences of altered cell behavior in tissue environments and effects of molecular therapeutics

Quantitative analysis of insulin-like growth factor 2 receptor and insulin-like growth factor binding proteins to identify control mechanisms for insulin-like growth factor 1 receptor phosphorylation

Experimental results for the determination of internalization rates for IGF1-IGF1R, IGF2-IGF1R, IGF2-IGF2R. (PDF 162 kb

A Subset of Secreted Proteins in Ascites Can Predict Platinum-Free Interval in Ovarian Cancer

The time between the last cycle of chemotherapy and recurrence, the platinum-free interval (PFI), predicts overall survival in high-grade serous ovarian cancer (HGSOC). To identify secreted proteins associated with a shorter PFI, we utilized machine learning to predict the PFI from ascites composition. Ascites from stage III/IV HGSOC patients treated with neoadjuvant chemotherapy (NACT) or primary debulking surgery (PDS) were screened for secreted proteins and Lasso regression models were built to predict the PFI. Through regularization techniques, the number of analytes used in each model was reduced; to minimize overfitting, we utilized an analysis of model robustness. This resulted in models with 26 analytes and a root-mean-square error (RMSE) of 19 days for the NACT cohort and 16 analytes and an RMSE of 7 days for the PDS cohort. High concentrations of MMP-2 and EMMPRIN correlated with a shorter PFI in the NACT patients, whereas high concentrations of uPA Urokinase and MMP-3 correlated with a shorter PFI in PDS patients. Our results suggest that the analysis of ascites may be useful for outcome prediction and identified factors in the tumor microenvironment that may lead to worse outcomes. Our approach to tuning for model stability, rather than only model accuracy, may be applicable to other biomarker discovery tasks

A Subset of Secreted Proteins in Ascites Can Predict Platinum-Free Interval in Ovarian Cancer

Simple SummaryIdentifying proteins that correlate with better or worse outcomes may help to identify new treatment approaches for advanced high-grade serous ovarian cancer. Here, we utilize a machine learning technique to correlate the levels of 58 secreted proteins in tumor ascites with the time to disease recurrence after chemotherapy, which is known clinically as the platinum-free interval. We identify several candidate proteins correlated to shorter or longer platinum-free intervals and describe model analysis methods that may be useful for other studies aiming to identify factors impacting patient outcomes. Future validation of these factors in a prospective cohort would confirm their clinical utility, whereas a study of the mechanisms that they impact may identify new therapies. The time between the last cycle of chemotherapy and recurrence, the platinum-free interval (PFI), predicts overall survival in high-grade serous ovarian cancer (HGSOC). To identify secreted proteins associated with a shorter PFI, we utilized machine learning to predict the PFI from ascites composition. Ascites from stage III/IV HGSOC patients treated with neoadjuvant chemotherapy (NACT) or primary debulking surgery (PDS) were screened for secreted proteins and Lasso regression models were built to predict the PFI. Through regularization techniques, the number of analytes used in each model was reduced; to minimize overfitting, we utilized an analysis of model robustness. This resulted in models with 26 analytes and a root-mean-square error (RMSE) of 19 days for the NACT cohort and 16 analytes and an RMSE of 7 days for the PDS cohort. High concentrations of MMP-2 and EMMPRIN correlated with a shorter PFI in the NACT patients, whereas high concentrations of uPA Urokinase and MMP-3 correlated with a shorter PFI in PDS patients. Our results suggest that the analysis of ascites may be useful for outcome prediction and identified factors in the tumor microenvironment that may lead to worse outcomes. Our approach to tuning for model stability, rather than only model accuracy, may be applicable to other biomarker discovery tasks.</p

Ten simple rules for developing a mentor–mentee expectations document

<p>Ten simple rules for developing a mentor–mentee expectations document</p

RAS Mutations Impact TNF-Induced Apoptosis in Colon Carcinoma Cells via ERK-Modulatory Negative and Positive Feedback Circuits along with non-ERK Pathway Effects

More than 40% of colon cancers have a mutation in K-RAS or N-RAS, GTPases that operate as central hubs for multiple key signaling pathways within the cell. Utilizing an isogenic panel of colon carcinoma cells with K-RAS or N-RAS variations, we observed differences in tumor necrosis factor-α (TNFα)–induced apoptosis. When the dynamics of phosphorylated ERK response to TNFα were examined, K-RAS mutant cells showed lower activation whereas N-RAS mutant cells exhibited prolonged duration. These divergent trends were partially explained by differential induction of two ERK-modulatory circuits: negative feedback mediated by dual-specificity phosphatase 5 and positive feedback by autocrine transforming growth factor-α. Moreover, in the various RAS mutant colon carcinoma lines, the transforming growth factor-α autocrine loop differentially elicited a further downstream chemokine (CXCL1/CXCL8) autocrine loop, with the two loops having opposite effects on apoptosis. Although the apoptotic responses of the RAS mutant panel to TNFα treatment showed significant dependence on the respective phosphorylated ERK dynamics, successful prediction across the various cell lines required contextual information concerning additional pathways including IKK and p38. A quantitative computational model based on weighted linear combinations of these pathway activities successfully predicted not only the spectrum of cell death responses but also the corresponding chemokine production responses. Our findings indicate that diverse RAS mutations yield differential cell behavioral responses to inflammatory cytokine exposure by means of (a) differential effects on ERK activity via multiple feedback circuit mechanisms, and (b) differential effects on other key signaling pathways contextually modulating ERK-related dependence. [Cancer Res 2009;69(20):8191–9]National Institutes of Health. (U.S.) (U54-CA112967)National Institutes of Health. (U.S.) (P50-GM68762)American Cancer Society (PF-08-026-01-CCG