TY - JOUR T1 - Gene Expression Integration into Pathway Modules Reveals a Pan-Cancer Metabolic Landscape. JF - Cancer Res Y1 - 2018 A1 - Cubuk, Cankut A1 - Hidalgo, Marta R A1 - Amadoz, Alicia A1 - Pujana, Miguel A A1 - Mateo, Francesca A1 - Herranz, Carmen A1 - Carbonell-Caballero, José A1 - Dopazo, Joaquin KW - Cell Line, Tumor KW - Cluster Analysis KW - Disease Progression KW - Gene Expression Profiling KW - Gene Expression Regulation, Neoplastic KW - Gene Regulatory Networks KW - Humans KW - Kaplan-Meier Estimate KW - Metabolome KW - mutation KW - Neoplasms KW - Oncogenes KW - Phenotype KW - Prognosis KW - RNA, Small Interfering KW - Sequence Analysis, RNA KW - Transcriptome KW - Treatment Outcome AB -

Metabolic reprogramming plays an important role in cancer development and progression and is a well-established hallmark of cancer. Despite its inherent complexity, cellular metabolism can be decomposed into functional modules that represent fundamental metabolic processes. Here, we performed a pan-cancer study involving 9,428 samples from 25 cancer types to reveal metabolic modules whose individual or coordinated activity predict cancer type and outcome, in turn highlighting novel therapeutic opportunities. Integration of gene expression levels into metabolic modules suggests that the activity of specific modules differs between cancers and the corresponding tissues of origin. Some modules may cooperate, as indicated by the positive correlation of their activity across a range of tumors. The activity of many metabolic modules was significantly associated with prognosis at a stronger magnitude than any of their constituent genes. Thus, modules may be classified as tumor suppressors and oncomodules according to their potential impact on cancer progression. Using this modeling framework, we also propose novel potential therapeutic targets that constitute alternative ways of treating cancer by inhibiting their reprogrammed metabolism. Collectively, this study provides an extensive resource of predicted cancer metabolic profiles and dependencies. Combining gene expression with metabolic modules identifies molecular mechanisms of cancer undetected on an individual gene level and allows discovery of new potential therapeutic targets. .

VL - 78 IS - 21 U1 - https://www.ncbi.nlm.nih.gov/pubmed/30135189?dopt=Abstract ER - TY - JOUR T1 - The protease MT1-MMP drives a combinatorial proteolytic program in activated endothelial cells. JF - FASEB J Y1 - 2012 A1 - Koziol, Agnieszka A1 - Gonzalo, Pilar A1 - Mota, Alba A1 - Pollán, Angela A1 - Lorenzo, Cristina A1 - Colomé, Nuria A1 - Montaner, David A1 - Dopazo, Joaquin A1 - Arribas, Joaquín A1 - Canals, Francesc A1 - Arroyo, Alicia G KW - Animals KW - Blotting, Western KW - Combinatorial Chemistry Techniques KW - Computational Biology KW - Endothelial Cells KW - Gene Expression Regulation, Enzymologic KW - Inflammation KW - Matrix Metalloproteinase 14 KW - Mice KW - Protein Array Analysis KW - Reverse Transcriptase Polymerase Chain Reaction KW - RNA Interference KW - RNA, Small Interfering KW - Transcriptome KW - Tumor Necrosis Factor-alpha AB -

The mechanism by which proteolytic events translate into biological responses is not well understood. To explore the link of pericellular proteolysis to events relevant to capillary sprouting within the inflammatory context, we aimed at the identification of the collection of substrates of the protease MT1-MMP in endothelial tip cells induced by inflammatory stimuli. We applied quantitative proteomics to endothelial cells (ECs) derived from wild-type and MT1-MMP-null mice to identify the substrate repertoire of this protease in TNF-α-activated ECs. Bioinformatics analysis revealed a combinatorial MT1-MMP proteolytic program, in which combined rather than single substrate processing would determine biological decisions by activated ECs, including chemotaxis, cell motility and adhesion, and vasculature development. MT1-MMP-deficient ECs inefficiently processed several of these substrates (TSP1, CYR61, NID1, and SEM3C), validating the model. This novel concept of MT1-MMP-driven combinatorial proteolysis in angiogenesis might be extendable to proteolytic actions in other cellular contexts.

VL - 26 IS - 11 U1 - https://www.ncbi.nlm.nih.gov/pubmed/22859368?dopt=Abstract ER -