SUMMARY Systematic characterization of cancer genomes has revealed a staggering number of diverse aberrations that differ among individuals, such that the functional importance and physiological impact of most tumor genetic alterations remains poorly defined. We developed a computational framework that integrates chromosomal copy number and gene expression data for detecting aberrations that promote cancer progression. We demonstrate the utility of this framework using a melanoma dataset. Our analysis correctly identified known drivers of melanoma and predicted multiple novel tumor dependencies. Two dependencies, TBC1D16 and RAB27A, confirmed empirically, suggest that abnormal regulation of protein trafficking contributes to proliferation in melanoma. Together, these results demonstrate the ability of integrative Bayesian approaches to identify novel candidate drivers with biological, and possibly therapeutic, importance in cancer.
BackgroundGlutamine metabolism is a central metabolic pathway in cancer. Recently, reductive carboxylation of glutamine for lipogenesis has been shown to constitute a key anabolic route in cancer cells. However, little is known regarding central regulators of the various glutamine metabolic pathways in cancer cells.MethodsThe impact of PGC-1α and ERRα on glutamine enzyme expression was assessed in ERBB2+ breast cancer cell lines with quantitative RT-PCR, chromatin immunoprecipitation, and immunoblotting experiments. Glutamine flux was quantified using 13C-labeled glutamine and GC/MS analyses. Functional assays for lipogenesis were performed using 14C-labeled glutamine. The expression of glutamine metabolism genes in breast cancer patients was determined by bioinformatics analyses using The Cancer Genome Atlas.ResultsWe show that the transcriptional coactivator PGC-1α, along with the transcription factor ERRα, is a positive regulator of the expression of glutamine metabolism genes in ERBB2+ breast cancer. Indeed, ERBB2+ breast cancer cells with increased expression of PGC-1α display elevated expression of glutamine metabolism genes. Furthermore, ERBB2+ breast cancer cells with reduced expression of PGC-1α or when treated with C29, a pharmacological inhibitor of ERRα, exhibit diminished expression of glutamine metabolism genes. The biological relevance of the control of glutamine metabolism genes by the PGC-1α/ERRα axis is demonstrated by consequent regulation of glutamine flux through the citric acid cycle. PGC-1α and ERRα regulate both the canonical citric acid cycle (forward) and the reductive carboxylation (reverse) fluxes; the latter can be used to support de novo lipogenesis reactions, most notably in hypoxic conditions. Importantly, murine and human ERBB2+ cells lines display a significant dependence on glutamine availability for their growth. Finally, we show that PGC-1α expression is positively correlated with that of the glutamine pathway in ERBB2+ breast cancer patients, and high expression of this pathway is associated with reduced patient survival.ConclusionsThese data reveal that the PGC-1α/ERRα axis is a central regulator of glutamine metabolism in ERBB2+ breast cancer. This novel regulatory link, as well as the marked reduction in patient survival time associated with increased glutamine pathway gene expression, suggests that targeting glutamine metabolism may have therapeutic potential in the treatment of ERBB2+ breast cancer.
Cell death is a complex process that plays a vital role in development, homeostasis, and disease. Our understanding of and ability to control cell death is impeded by an incomplete characterization of the full range of cell death processes that occur in mammalian systems, especially in response to exogenous perturbations. We present here a general approach to address this problem, which we call modulatory profiling. Modulatory profiles are composed of the changes in potency and efficacy of lethal compounds produced by a second cell death-modulating agent in human cell lines. We show that compounds with the same characterized mechanism of action have similar modulatory profiles. Furthermore, clustering of modulatory profiles revealed relationships not evident when clustering lethal compounds based on gene expression profiles alone. Finally, modulatory profiling of compounds correctly predicted three previously uncharacterized compounds to be microtubule-destabilizing agents, classified numerous compounds that act nonspecifically, and identified compounds that cause cell death through a mechanism that is morphologically and biochemically distinct from previously established ones.apoptosis | chemical biology | small molecules C ell death has historically been viewed as a binary phenomenon. Cells were described to die in one of two ways-through a controlled and ordered process (apoptosis) or an unregulated and chaotic process (necrosis) (1, 2). Not only were these often considered the only two possible mechanisms, but they were also frequently viewed as morphologically and biochemically uniform (3, 4). A great deal of research in recent decades has not only shown the complexity and heterogeneity of apoptotic and necrotic signaling, but also that cells can die in physiological and nonphysiological contexts through processes morphologically and biochemically distinct from both apoptosis and necrosis.Activation of caspases, a family of cysteine proteases, is essential for producing the full morphological characteristics of apoptosis. There are at least three distinct pathways that can lead to the activation of effector caspases-the extrinsic death receptor pathway, the intrinsic mitochondrial pathway, and the Granzyme B pathway (5)-but numerous mechanisms feed into these three pathways. There is substantial evidence that necrosis, long considered to be a disorganized and unregulated process, can proceed through an evolutionarily conserved pathway in a highly orchestrated fashion. Necrosis-like morphology has been observed after death receptor stimulation (6-12), after treatment with DNA-damaging agents (13-15), and in Caenorhabditis elegans in response to a variety of stresses (16,17). These examples illustrate the heterogeneity of cell death processes resembling necrosis. A widely debated nonapoptotic, nonnecrotic cell death mechanism is autophagic cell death, which has been implicated in vivo in the involution of the salivary gland in Drosophila (18) and in death because of the hypersensitivity response in Arabidopsi...
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