%0 Journal Article %J Cells %D 2020 %T Mechanistic Models of Signaling Pathways Reveal the Drug Action Mechanisms behind Gender-Specific Gene Expression for Cancer Treatments. %A Cubuk, Cankut %A Can, Fatma E %A Peña-Chilet, Maria %A Dopazo, Joaquin %K Female %K Gene Expression Regulation, Neoplastic %K Humans %K Male %K Neoplasms %K Signal Transduction %X

Despite the existence of differences in gene expression across numerous genes between males and females having been known for a long time, these have been mostly ignored in many studies, including drug development and its therapeutic use. In fact, the consequences of such differences over the disease mechanisms or the drug action mechanisms are completely unknown. Here we applied mechanistic mathematical models of signaling activity to reveal the ultimate functional consequences that gender-specific gene expression activities have over cell functionality and fate. Moreover, we also used the mechanistic modeling framework to simulate the drug interventions and unravel how drug action mechanisms are affected by gender-specific differential gene expression. Interestingly, some cancers have many biological processes significantly affected by these gender-specific differences (e.g., bladder or head and neck carcinomas), while others (e.g., glioblastoma or rectum cancer) are almost insensitive to them. We found that many of these gender-specific differences affect cancer-specific pathways or in physiological signaling pathways, also involved in cancer origin and development. Finally, mechanistic models have the potential to be used for finding alternative therapeutic interventions on the pathways targeted by the drug, which lead to similar results compensating the downstream consequences of gender-specific differences in gene expression.

%B Cells %V 9 %8 2020 06 29 %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/32610626?dopt=Abstract %R 10.3390/cells9071579 %0 Journal Article %J Cancer Res %D 2018 %T Gene Expression Integration into Pathway Modules Reveals a Pan-Cancer Metabolic Landscape. %A Cubuk, Cankut %A Hidalgo, Marta R %A Amadoz, Alicia %A Pujana, Miguel A %A Mateo, Francesca %A Herranz, Carmen %A Carbonell-Caballero, José %A Dopazo, Joaquin %K Cell Line, Tumor %K Cluster Analysis %K Disease Progression %K Gene Expression Profiling %K Gene Expression Regulation, Neoplastic %K Gene Regulatory Networks %K Humans %K Kaplan-Meier Estimate %K Metabolome %K mutation %K Neoplasms %K Oncogenes %K Phenotype %K Prognosis %K RNA, Small Interfering %K Sequence Analysis, RNA %K Transcriptome %K Treatment Outcome %X

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. .

%B Cancer Res %V 78 %P 6059-6072 %8 2018 11 01 %G eng %N 21 %1 https://www.ncbi.nlm.nih.gov/pubmed/30135189?dopt=Abstract %R 10.1158/0008-5472.CAN-17-2705 %0 Journal Article %J Biol Direct %D 2018 %T Models of cell signaling uncover molecular mechanisms of high-risk neuroblastoma and predict disease outcome. %A Hidalgo, Marta R %A Amadoz, Alicia %A Cubuk, Cankut %A Carbonell-Caballero, José %A Dopazo, Joaquin %K Computational Biology %K Gene Expression Regulation, Neoplastic %K Humans %K JNK Mitogen-Activated Protein Kinases %K Models, Theoretical %K Neuroblastoma %K Signal Transduction %X

BACKGROUND: Despite the progress in neuroblastoma therapies the mortality of high-risk patients is still high (40-50%) and the molecular basis of the disease remains poorly known. Recently, a mathematical model was used to demonstrate that the network regulating stress signaling by the c-Jun N-terminal kinase pathway played a crucial role in survival of patients with neuroblastoma irrespective of their MYCN amplification status. This demonstrates the enormous potential of computational models of biological modules for the discovery of underlying molecular mechanisms of diseases.

RESULTS: Since signaling is known to be highly relevant in cancer, we have used a computational model of the whole cell signaling network to understand the molecular determinants of bad prognostic in neuroblastoma. Our model produced a comprehensive view of the molecular mechanisms of neuroblastoma tumorigenesis and progression.

CONCLUSION: We have also shown how the activity of signaling circuits can be considered a reliable model-based prognostic biomarker.

REVIEWERS: This article was reviewed by Tim Beissbarth, Wenzhong Xiao and Joanna Polanska. For the full reviews, please go to the Reviewers' comments section.

%B Biol Direct %V 13 %P 16 %8 2018 08 22 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/30134948?dopt=Abstract %R 10.1186/s13062-018-0219-4 %0 Journal Article %J PLoS One %D 2013 %T Mammosphere formation in breast carcinoma cell lines depends upon expression of E-cadherin. %A Manuel Iglesias, Juan %A Beloqui, Izaskun %A Garcia-Garcia, Francisco %A Leis, Olatz %A Vazquez-Martin, Alejandro %A Eguiara, Arrate %A Cufi, Silvia %A Pavon, Andres %A Menendez, Javier A %A Dopazo, Joaquin %A Martin, Angel G %K Breast Neoplasms %K Cadherins %K Cell Line, Tumor %K Cell Proliferation %K Cluster Analysis %K Female %K gene expression %K Gene Expression Profiling %K Gene Expression Regulation, Neoplastic %K Gene Knockdown Techniques %K Humans %K MCF-7 Cells %K Neoplastic Stem Cells %K Spheroids, Cellular %K Tumor Cells, Cultured %X

Tumors are heterogeneous at the cellular level where the ability to maintain tumor growth resides in discrete cell populations. Floating sphere-forming assays are broadly used to test stem cell activity in tissues, tumors and cell lines. Spheroids are originated from a small population of cells with stem cell features able to grow in suspension culture and behaving as tumorigenic in mice. We tested the ability of eleven common breast cancer cell lines representing the major breast cancer subtypes to grow as mammospheres, measuring the ability to maintain cell viability upon serial non-adherent passage. Only MCF7, T47D, BT474, MDA-MB-436 and JIMT1 were successfully propagated as long-term mammosphere cultures, measured as the increase in the number of viable cells upon serial non-adherent passages. Other cell lines tested (SKBR3, MDA-MB-231, MDA-MB-468 and MDA-MB-435) formed cell clumps that can be disaggregated mechanically, but cell viability drops dramatically on their second passage. HCC1937 and HCC1569 cells formed typical mammospheres, although they could not be propagated as long-term mammosphere cultures. All the sphere forming lines but MDA-MB-436 express E-cadherin on their surface. Knock down of E-cadherin expression in MCF-7 cells abrogated its ability to grow as mammospheres, while re-expression of E-cadherin in SKBR3 cells allow them to form mammospheres. Therefore, the mammosphere assay is suitable to reveal stem like features in breast cancer cell lines that express E-cadherin.

%B PLoS One %V 8 %P e77281 %8 2013 %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/24124614?dopt=Abstract %R 10.1371/journal.pone.0077281 %0 Journal Article %J Exp Dermatol %D 2013 %T Role of CPI-17 in restoring skin homoeostasis in cutaneous field of cancerization: effects of topical application of a film-forming medical device containing photolyase and UV filters. %A Puig-Butille, Joan Anton %A Malvehy, Josep %A Potrony, Miriam %A Trullas, Carles %A Garcia-Garcia, Francisco %A Dopazo, Joaquin %A Puig, Susana %K Administration, Topical %K Adult %K Aged %K Aged, 80 and over %K Biopsy %K Deoxyribodipyrimidine Photo-Lyase %K Female %K Gene Expression Profiling %K Gene Expression Regulation, Enzymologic %K Gene Expression Regulation, Neoplastic %K Homeostasis %K Humans %K Inflammation %K Intracellular Signaling Peptides and Proteins %K Liposomes %K Male %K Middle Aged %K Muscle Proteins %K Phenotype %K Phosphoprotein Phosphatases %K Reactive Oxygen Species %K Skin %K Skin Neoplasms %K Ultraviolet Rays %X

Cutaneous field of cancerization (CFC) is caused in part by the carcinogenic effect of the cyclobutane pyrimidine dimers CPD and 6-4 photoproducts (6-4PPs). Photoreactivation is carried out by photolyases which specifically recognize and repair both photoproducts. The study evaluates the molecular effects of topical application of a film-forming medical device containing photolyase and UV filters on the precancerous field in AK from seven patients. Skin improvement after treatment was confirmed in all patients by histopathological and molecular assessment. A gene set analysis showed that skin recovery was associated with biological processes involved in tissue homoeostasis and cell maintenance. The CFC response was associated with over-expression of the CPI-17 gene, and a dependence on the initial expression level was observed (P = 0.001). Low CPI-17 levels were directly associated with pro-inflammatory genes such as TNF (P = 0.012) and IL-1B (P = 0.07). Our results suggest a role for CPI-17 in restoring skin homoeostasis in CFC lesions.

%B Exp Dermatol %V 22 %P 494-6 %8 2013 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/23800065?dopt=Abstract %R 10.1111/exd.12177 %0 Journal Article %J Oncogene %D 2008 %T Molecular profiling related to poor prognosis in thyroid carcinoma. Combining gene expression data and biological information. %A Montero-Conde, C %A Martín-Campos, J M %A Lerma, E %A Gimenez, G %A Martínez-Guitarte, J L %A Combalía, N %A Montaner, D %A Matías-Guiu, X %A Dopazo, J %A de Leiva, A %A Robledo, M %A Mauricio, D %K Adenoma %K Adolescent %K Adult %K Aged %K Biomarkers, Tumor %K Carcinoma %K Carcinoma, Papillary %K Cell Differentiation %K Female %K Gene Expression Profiling %K Gene Expression Regulation, Neoplastic %K Humans %K Male %K Middle Aged %K Oligonucleotide Array Sequence Analysis %K Prognosis %K Reverse Transcriptase Polymerase Chain Reaction %K RNA, Neoplasm %K Signal Transduction %K Thyroid Neoplasms %X

Undifferentiated and poorly differentiated thyroid tumors are responsible for more than half of thyroid cancer patient deaths in spite of their low incidence. Conventional treatments do not obtain substantial benefits, and the lack of alternative approaches limits patient survival. Additionally, the absence of prognostic markers for well-differentiated tumors complicates patient-specific treatments and favors the progression of recurrent forms. In order to recognize the molecular basis involved in tumor dedifferentiation and identify potential markers for thyroid cancer prognosis prediction, we analysed the expression profile of 44 thyroid primary tumors with different degrees of dedifferentiation and aggressiveness using cDNA microarrays. Transcriptome comparison of dedifferentiated and well-differentiated thyroid tumors identified 1031 genes with >2-fold difference in absolute values and false discovery rate of <0.15. According to known molecular interaction and reaction networks, the products of these genes were mainly clustered in the MAPkinase signaling pathway, the TGF-beta signaling pathway, focal adhesion and cell motility, activation of actin polymerization and cell cycle. An exhaustive search in several databases allowed us to identify various members of the matrix metalloproteinase, melanoma antigen A and collagen gene families within the upregulated gene set. We also identified a prognosis classifier comprising just 30 transcripts with an overall accuracy of 95%. These findings may clarify the molecular mechanisms involved in thyroid tumor dedifferentiation and provide a potential prognosis predictor as well as targets for new therapies.

%B Oncogene %V 27 %P 1554-61 %8 2008 Mar 06 %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/17873908?dopt=Abstract %R 10.1038/sj.onc.1210792 %0 Journal Article %J BMC Genomics %D 2007 %T Evidence for systems-level molecular mechanisms of tumorigenesis. %A Hernández, Pilar %A Huerta-Cepas, Jaime %A Montaner, David %A Al-Shahrour, Fátima %A Valls, Joan %A Gómez, Laia %A Capellà, Gabriel %A Dopazo, Joaquin %A Pujana, Miguel Angel %K Cell Transformation, Neoplastic %K Gene Expression Profiling %K Gene Expression Regulation, Neoplastic %K Humans %K Male %K Models, Biological %K Models, Genetic %K Models, Statistical %K Neoplasm Proteins %K Neoplasms %K Prostatic Neoplasms %K Protein Interaction Mapping %K RNA, Messenger %K Signal Transduction %K Systems biology %X

BACKGROUND: Cancer arises from the consecutive acquisition of genetic alterations. Increasing evidence suggests that as a consequence of these alterations, molecular interactions are reprogrammed in the context of highly connected and regulated cellular networks. Coordinated reprogramming would allow the cell to acquire the capabilities for malignant growth.

RESULTS: Here, we determine the coordinated function of cancer gene products (i.e., proteins encoded by differentially expressed genes in tumors relative to healthy tissue counterparts, hereafter referred to as "CGPs") defined as their topological properties and organization in the interactome network. We show that CGPs are central to information exchange and propagation and that they are specifically organized to promote tumorigenesis. Centrality is identified by both local (degree) and global (betweenness and closeness) measures, and systematically appears in down-regulated CGPs. Up-regulated CGPs do not consistently exhibit centrality, but both types of cancer products determine the overall integrity of the network structure. In addition to centrality, down-regulated CGPs show topological association that correlates with common biological processes and pathways involved in tumorigenesis.

CONCLUSION: Given the current limited coverage of the human interactome, this study proposes that tumorigenesis takes place in a specific and organized way at the molecular systems-level and suggests a model that comprises the precise down-regulation of groups of topologically-associated proteins involved in particular functions, orchestrated with the up-regulation of specific proteins.

%B BMC Genomics %V 8 %P 185 %8 2007 Jun 20 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/17584915?dopt=Abstract %R 10.1186/1471-2164-8-185