RESUMO
Despite recent advancements in the treatment of multiple myeloma (MM), nearly all patients ultimately relapse and many become refractory to multiple lines of therapies. Therefore, we not only need the ability to predict which patients are at high risk for disease progression but also a means to understand the mechanisms underlying their risk. Here, we report a transcriptional regulatory network (TRN) for MM inferred from cross-sectional multi-omics data from 881 patients that predicts how 124 chromosomal abnormalities and somatic mutations causally perturb 392 transcription regulators of 8549 genes to manifest in distinct clinical phenotypes and outcomes. We identified 141 genetic programs whose activity profiles stratify patients into 25 distinct transcriptional states and proved to be more predictive of outcomes than did mutations. The coherence of these programs and accuracy of our network-based risk prediction was validated in two independent datasets. We observed subtype-specific vulnerabilities to interventions with existing drugs and revealed plausible mechanisms for relapse, including the establishment of an immunosuppressive microenvironment. Investigation of the t(4;14) clinical subtype using the TRN revealed that 16% of these patients exhibit an extreme-risk combination of genetic programs (median progression-free survival of 5 months) that create a distinct phenotype with targetable genes and pathways.
RESUMO
BACKGROUND: Mechanistic models, when combined with pertinent data, can improve our knowledge regarding important molecular and cellular mechanisms found in cancer. These models make the prediction of tissue-level response to drug treatment possible, which can lead to new therapies and improved patient outcomes. Here we present a data-driven multiscale modeling framework to study molecular interactions between cancer, stromal, and immune cells found in the tumor microenvironment. We also develop methods to use molecular data available in The Cancer Genome Atlas to generate sample-specific models of cancer. RESULTS: By combining published models of different cells relevant to pancreatic ductal adenocarcinoma (PDAC), we built an agent-based model of the multicellular pancreatic tumor microenvironment, formally describing cell type-specific molecular interactions and cytokine-mediated cell-cell communications. We used an ensemble-based modeling approach to systematically explore how variations in the tumor microenvironment affect the viability of cancer cells. The results suggest that the autocrine loop involving EGF signaling is a key interaction modulator between pancreatic cancer and stellate cells. EGF is also found to be associated with previously described subtypes of PDAC. Moreover, the model allows a systematic exploration of the effect of possible therapeutic perturbations; our simulations suggest that reducing bFGF secretion by stellate cells will have, on average, a positive impact on cancer apoptosis. CONCLUSIONS: The developed framework allows model-driven hypotheses to be generated regarding therapeutically relevant PDAC states with potential molecular and cellular drivers indicating specific intervention strategies.
Assuntos
Algoritmos , Carcinoma Ductal Pancreático/etiologia , Carcinoma Ductal Pancreático/patologia , Suscetibilidade a Doenças , Modelos Biológicos , Comunicação Autócrina , Carcinoma Ductal Pancreático/metabolismo , Comunicação Celular/genética , Citocinas/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Especificidade de Órgãos , Comunicação Parácrina , FenótipoRESUMO
Failure to clear antigens causes CD8+ T cells to become increasingly hypo-functional, a state known as exhaustion. We combined manually extracted information from published literature with gene expression data from diverse model systems to infer a set of molecular regulatory interactions that underpin exhaustion. Topological analysis and simulation modeling of the network suggests CD8+ T cells undergo 2 major transitions in state following stimulation. The time cells spend in the earlier pro-memory/proliferative (PP) state is a fixed and inherent property of the network structure. Transition to the second state is necessary for exhaustion. Combining insights from network topology analysis and simulation modeling, we predict the extent to which each node in our network drives cells towards an exhausted state. We demonstrate the utility of our approach by experimentally testing the prediction that drug-induced interference with EZH2 function increases the proportion of pro-memory/proliferative cells in the early days post-activation.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Redes Reguladoras de Genes/imunologia , Modelos Imunológicos , Animais , Linfócitos T CD8-Positivos/metabolismo , Simulação por Computador , Conjuntos de Dados como Assunto , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Memória Imunológica/efeitos dos fármacos , Memória Imunológica/imunologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , RNA-Seq , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologiaRESUMO
While the past decade has seen meaningful improvements in clinical outcomes for multiple myeloma patients, a subset of patients does not benefit from current therapeutics for unclear reasons. Many gene expression-based models of risk have been developed, but each model uses a different combination of genes and often involves assaying many genes making them difficult to implement. We organized the Multiple Myeloma DREAM Challenge, a crowdsourced effort to develop models of rapid progression in newly diagnosed myeloma patients and to benchmark these against previously published models. This effort lead to more robust predictors and found that incorporating specific demographic and clinical features improved gene expression-based models of high risk. Furthermore, post-challenge analysis identified a novel expression-based risk marker, PHF19, which has recently been found to have an important biological role in multiple myeloma. Lastly, we show that a simple four feature predictor composed of age, ISS, and expression of PHF19 and MMSET performs similarly to more complex models with many more gene expression features included.
Assuntos
Biomarcadores Tumorais/metabolismo , Ensaios Clínicos como Assunto/estatística & dados numéricos , Proteínas de Ligação a DNA/metabolismo , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Modelos Estatísticos , Mieloma Múltiplo/patologia , Fatores de Transcrição/metabolismo , Biomarcadores Tumorais/genética , Ciclo Celular , Proliferação de Células , Proteínas de Ligação a DNA/genética , Bases de Dados Factuais , Conjuntos de Dados como Assunto , Humanos , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Fatores de Transcrição/genética , Células Tumorais CultivadasRESUMO
Uncovering pathways underlying drug-induced toxicity is a fundamental objective in the field of toxicogenomics. Developing mechanism-based toxicity biomarkers requires the identification of such novel pathways and the order of their sufficiency in causing a phenotypic response. Genome-wide RNA interference (RNAi) phenotypic screening has emerged as an effective tool in unveiling the genes essential for specific cellular functions and biological activities. However, eliciting the relative contribution of and sufficiency relationships among the genes identified remains challenging. In the rodent, the most widely used animal model in preclinical studies, it is unrealistic to exhaustively examine all potential interactions by RNAi screening. Application of existing computational approaches to infer regulatory networks with biological outcomes in the rodent is limited by the requirements for a large number of targeted permutations. Therefore, we developed a two-step relay method that requires only one targeted perturbation for genome-wide de novo pathway discovery. Using expression profiles in response to small interfering RNAs (siRNAs) against the gene for peroxisome proliferator-activated receptor alpha (Ppara), our method unveiled the potential causal sufficiency order network for liver hypertrophy in the rodent. The validity of the inferred 16 causal transcripts or 15 known genes for PPARalpha-induced liver hypertrophy is supported by their ability to predict non-PPARalpha-induced liver hypertrophy with 84% sensitivity and 76% specificity. Simulation shows that the probability of achieving such predictive accuracy without the inferred causal relationship is exceedingly small (p < 0.005). Five of the most sufficient causal genes have been previously disrupted in mouse models; the resulting phenotypic changes in the liver support the inferred causal roles in liver hypertrophy. Our results demonstrate the feasibility of defining pathways mediating drug-induced toxicity from siRNA-treated expression profiles. When combined with phenotypic evaluation, our approach should help to unleash the full potential of siRNAs in systematically unveiling the molecular mechanism of biological events.
Assuntos
Inativação Gênica , Fígado/metabolismo , Fígado/patologia , Modelos Biológicos , PPAR alfa/metabolismo , Proteoma/metabolismo , RNA Interferente Pequeno/genética , Animais , Simulação por Computador , Perfilação da Expressão Gênica/métodos , Hipertrofia/induzido quimicamente , Hipertrofia/metabolismo , Fígado/efeitos dos fármacos , Camundongos , PPAR alfa/genética , RNA Interferente Pequeno/administração & dosagem , Transdução de SinaisRESUMO
MOTIVATION: In microarray gene expression studies, the number of replicated microarrays is usually small because of cost and sample availability, resulting in unreliable variance estimation and thus unreliable statistical hypothesis tests. The unreliable variance estimation is further complicated by the fact that the technology-specific variance is intrinsically intensity-dependent. RESULTS: The Rosetta error model captures the variance-intensity relationship for various types of microarray technologies, such as single-color arrays and two-color arrays. This error model conservatively estimates intensity error and uses this value to stabilize the variance estimation. We present two commonly used error models: the intensity error-model for single-color microarrays and the ratio error model for two-color microarrays or ratios built from two single-color arrays. We present examples to demonstrate the strength of our error models in improving statistical power of microarray data analysis, particularly, in increasing expression detection sensitivity and specificity when the number of replicates is limited.