scholarly journals An immunoevasive strategy through clinically-relevant pan-cancer genomic and transcriptomic alterations of JAK-STAT signaling components

2019 ◽  
Author(s):  
Wai Hoong Chang ◽  
Alvina G. Lai
Keyword(s):  
Genetic Alterations ◽  
Janus Kinase ◽  
Renal Tumors ◽  
Molecular Features ◽  
Wide Range ◽  
Stat Signaling ◽  
Cancer Types ◽  
Endometrial Cancers ◽  
Pan Cancer ◽  
Stat Pathway

Since its discovery almost three decades ago, the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway has paved the road for understanding inflammatory and immunity processes related to a wide range of human pathologies including cancer. Several studies have demonstrated the importance of JAK-STAT pathway components in regulating tumor initiation and metastatic progression, yet, the extent of how genetic alterations influence patient outcome is far from being understood. Focusing on 133 genes involved in JAK-STAT signaling, we found that copy number alterations underpin transcriptional dysregulation that differs within and between cancer types. Integrated analyses on over 18,000 tumors representing 21 cancer types revealed a core set of 28 JAK-STAT pathway genes that correlated with survival outcomes in brain, renal, lung and endometrial cancers. High JAK-STAT scores were associated with increased mortality rates in brain and renal cancers, but not in lung and endometrial cancers where hyperactive JAK-STAT signaling is a positive prognostic factor. Patients with aberrant JAK-STAT signaling demon-strated pan-cancer molecular features associated with misex-pression of genes in other oncogenic pathways (Wnt, MAPK, TGF-β, PPAR and VEGF). Brain and renal tumors with hyperactive JAK-STAT signaling had increased regulatory T cell gene (Treg) expression. A combined model uniting JAK-STAT and Tregs allowed further delineation of risk groups where patients with high JAK-STAT and Treg scores consistently performed the worst. Providing a pan-cancer perspective of clinically-relevant JAK-STAT alterations, this study could serve as a framework for future research investigating anti-tumor immunity using combination therapy involving JAK-STAT and immune checkpoint inhibitors.

scholarly journals An immunoevasive strategy through clinically-relevant pan-cancer genomic and transcriptomic alterations of JAK-STAT signaling components

2019 ◽  
Vol 25 (1) ◽  
Author(s):  
Wai Hoong Chang ◽  
Alvina G. Lai
Keyword(s):  
Genetic Alterations ◽  
Janus Kinase ◽  
Renal Tumors ◽  
Survival Outcomes ◽  
Core Set ◽  
Stat Signaling ◽  
Cancer Types ◽  
Endometrial Cancers ◽  
Pan Cancer ◽  
Stat Pathway

Abstract Background Since its discovery almost three decades ago, the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway has paved the road for understanding inflammatory and immunity processes related to a wide range of human pathologies including cancer. Several studies have demonstrated the importance of JAK-STAT pathway components in regulating tumor initiation and metastatic progression, yet, the extent of how genetic alterations influence patient outcome is far from being understood. Methods Focusing on 133 genes involved in JAK-STAT signaling, we investigated genomic, transcriptomic and clinical profiles of over 18,000 patients representing 21 diverse cancer types. We identified a core set of 28 putative gain- or loss-of-function JAK-STAT genes that correlated with survival outcomes using Cox proportional hazards regression and Kaplan-Meier analyses. Differential expression analyses between high- and low-expressing patient groups were performed to evaluate the consequences of JAK-STAT misexpression. Results We found that copy number alterations underpinning transcriptional dysregulation of JAK-STAT pathway genes differ within and between cancer types. Integrated analyses uniting genomic and transcriptomic datasets revealed a core set of JAK-STAT pathway genes that correlated with survival outcomes in brain, renal, lung and endometrial cancers. High JAK-STAT scores were associated with increased mortality rates in brain and renal cancers, but not in lung and endometrial cancers where hyperactive JAK-STAT signaling is a positive prognostic factor. Patients with aberrant JAK-STAT signaling demonstrated pan-cancer molecular features associated with misexpression of genes in other oncogenic pathways (Wnt, MAPK, TGF-β, PPAR and VEGF). Brain and renal tumors with hyperactive JAK-STAT signaling had increased regulatory T cell gene (Treg) expression. A combined model uniting JAK-STAT and Tregs allowed further delineation of risk groups where patients with high JAK-STAT and Treg scores consistently performed the worst. Conclusion Providing a pan-cancer perspective of clinically-relevant JAK-STAT alterations, this study could serve as a framework for future research investigating anti-tumor immunity using combination therapy involving JAK-STAT and immune checkpoint inhibitors.

scholarly journals Flavivirus Nonstructural Protein NS5 Dysregulates HSP90 to Broadly Inhibit JAK/STAT Signaling

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 899 ◽  
Author(s):  
Justin A. Roby ◽  
Katharina Esser-Nobis ◽  
Elyse C. Dewey-Verstelle ◽  
Marian R. Fairgrieve ◽  
Johannes Schwerk ◽  
...  
Keyword(s):  
Nonstructural Protein ◽  
Heat Shock Protein 90 ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Critical Determinant ◽  
Wide Range ◽  
Stat Signaling ◽  
Virus West Nile ◽  
Flavivirus Infection ◽  
Stat Pathway

Pathogenic flaviviruses antagonize host cell Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling downstream of interferons α/β. Here, we show that flaviviruses inhibit JAK/STAT signaling induced by a wide range of cytokines beyond interferon, including interleukins. This broad inhibition was mapped to viral nonstructural protein 5 (NS5) binding to cellular heat shock protein 90 (HSP90), resulting in reduced Janus kinase–HSP90 interaction and thus destabilization of unchaperoned JAKs (and other kinase clients) of HSP90 during infection by Zika virus, West Nile virus, and Japanese encephalitis virus. Our studies implicate viral dysregulation of HSP90 and the JAK/STAT pathway as a critical determinant of cytokine signaling control during flavivirus infection.

scholarly journals Manipulation of JAK/STAT Signalling by High-Risk HPVs: Potential Therapeutic Targets for HPV-Associated Malignancies

Viruses ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 977 ◽  
Author(s):  
Ethan L. Morgan ◽  
Andrew Macdonald
Keyword(s):  
Immune Response ◽  
Cell Proliferation ◽  
Significant Proportion ◽  
Human Papillomaviruses ◽  
Janus Kinase ◽  
Signalling Pathways ◽  
Proliferative Potential ◽  
Promote Cell Proliferation ◽  
Wide Range ◽  
Stat Pathway

Human papillomaviruses (HPVs) are small, DNA viruses that cause around 5% of all cancers in humans, including almost all cervical cancer cases and a significant proportion of anogenital and oral cancers. The HPV oncoproteins E5, E6 and E7 manipulate cellular signalling pathways to evade the immune response and promote virus persistence. The Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway has emerged as a key mediator in a wide range of important biological signalling pathways, including cell proliferation, cell survival and the immune response. While STAT1 and STAT2 primarily drive immune signalling initiated by interferons, STAT3 and STAT5 have widely been linked to the survival and proliferative potential of a number of cancers. As such, the inhibition of STAT3 and STAT5 may offer a therapeutic benefit in HPV-associated cancers. In this review, we will discuss how HPV manipulates JAK/STAT signalling to evade the immune system and promote cell proliferation, enabling viral persistence and driving cancer development. We also discuss approaches to inhibit the JAK/STAT pathway and how these could potentially be used in the treatment of HPV-associated disease.

scholarly journals The use of Drosophila Melanogaster as a Model Organism to study the effect of Innate Immunity on Metabolism

2020 ◽  
Author(s):  
Abeer Mohbeddin ◽  
Nawar Haj Ahmed ◽  
Layla Kamareddine
Keyword(s):  
Drosophila Melanogaster ◽  
Fat Body ◽  
Model Organism ◽  
Fruit Fly ◽  
Janus Kinase ◽  
Signal Transducer ◽  
Metabolic Homeostasis ◽  
Stat Signaling ◽  
Stat Pathway

Apart from its traditional role in disease control, recent body of evidence has implicated a role of the immune system in regulating metabolic homeostasis. Owing to the importance of this “immune-metabolic alignment” in dictating a state of health or disease, a proper mechanistic understanding of this alignment is crucial in opening up for promising therapeutic approaches against a broad range of chronic, metabolic, and inflammatory disorders like obesity, diabetes, and inflammatory bowel syndrome. In this project, we addressed the role of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) innate immune pathway in regulating different metabolic parameters using the Drosophila melanogaster (DM) fruit fly model organism. Mutant JAK/STAT pathway flies with a systemic knockdown of either Domeless (Dome) [domeG0282], the receptor that activates JAK/STAT signaling, or the signal-transducer and activator of transcription protein at 92E (Stat92E) [stat92EEY10528], were used. The results of the study revealed that blocking JAK/STAT signaling alters the metabolic profile of mutant flies. Both domeG0282 and stat92EEY10528 mutants had an increase in body weight, lipid deprivation from their fat body (lipid storage organ in flies), irregular accumulation of lipid droplets in the gut, systemic elevation of glucose and triglyceride levels, and differential down-regulation in the relative gene expression of different peptide hormones (Tachykinin, Allatostatin C, and Diuretic hormone 31) known to regulate metabolic homeostasis in flies. Because the JAK/STAT pathway is evolutionary conserved between invertebrates and vertebrates, our potential findings in the fruit fly serves as a platform for further immune-metabolic translational studies in more complex mammalian systems including humans.

scholarly journals Balanced JAK/STAT signaling is critical to maintain the functional and structural integrity of the Drosophila respiratory epithelium

2020 ◽  
Author(s):  
Xiao Niu ◽  
Christine Fink ◽  
Kimberley Kallsen ◽  
Viktoria Mincheva ◽  
Sören Franzenburg ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Lung Diseases ◽  
Structural Changes ◽  
Structural Integrity ◽  
Respiratory Epithelium ◽  
Janus Kinase ◽  
Chronic Obstructive ◽  
Chronic Lung Diseases ◽  
Stat Signaling ◽  
Stat Pathway

SummarySignals mediated by the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway play a central role in maintaining homeostasis in a multitude of tissues. A large number of studies have shown that this role is particularly prominent in the lungs. Deregulation of the JAK/STAT signaling pathway is causally linked with various, mostly chronic, lung diseases, including lung cancer, asthma, and chronic obstructive pulmonary disease. To elucidate the molecular framework that explains how deregulated JAK/STAT signaling gives rise to pathogenic states, we used the fruit fly Drosophila as a model. While the JAK/STAT pathway is characterized by high structural diversity and complexity in vertebrates, it is relatively simple in Drosophila. The JAK/STAT pathway was active in almost all respiratory epithelial cells of larvae and adult flies. Stressful stimuli, such as cigarette smoke, evoked strong and regionalized activation of the JAK/STAT pathway, which was most likely driven by the concurrently induced ligand Unpaired 2. Inhibition of JAK/STAT signaling induced apoptotic processes in epithelial cells. The aforementioned chronic lung diseases are associated with increased activity of the JAK/STAT pathway and are treated with specific JAK inhibitors. Therefore, we investigated the effects of increased JAK/STAT signaling in the respiratory epithelium of Drosophila. Ectopic activation of the JAK/STAT pathway led to premature death at the larval or pupal stage. Furthermore, it induced major structural changes in epithelial cells, which almost completely lost their typical characteristics. These structural changes led to considerable thickening of the epithelium, substantial narrowing of the air-conducting space, and disruption of the tracheal epicuticular structure. Pharmacological interference of JAK/STAT signaling reverted this phenotype. Activation of the JAK/STAT pathway also affected vesicle-mediated transport, which led to erroneous trafficking of typical junction proteins. In summary, these results demonstrate that balanced JAK/STAT signaling is essential for the normal functionality of the respiratory epithelium and thus the entire organ. A basal level of JAK/STAT signaling is required for cellular processes such as growth and division. However, chronic overactivation of this signaling leads to massive structural changes that are closely related to pathologies typically seen in chronic inflammatory lung diseases.

scholarly journals Metastatic signaling of hypoxia-related genes across TCGA Pan-Cancer types

2020 ◽  
Author(s):  
Andrés López-Cortés ◽  
Patricia Guevara-Ramírez ◽  
Santiago Guerrero ◽  
Esteban Ortiz-Prado ◽  
Jennyfer M. García-Cárdenas ◽  
...  
Keyword(s):  
Strong Association ◽  
Shortest Paths ◽  
Tumor Hypoxia ◽  
Tumor Stage ◽  
Ppi Network ◽  
Genomic Alterations ◽  
Cancer Driver ◽  
Molecular Features ◽  
Cancer Types ◽  
Pan Cancer

ABSTRACTMany primary-tumor subregions have low levels of molecular oxygen, termed hypoxia. Hypoxic tumors are at elevated risk for local failure and distant metastasis. Metastatic disease is the leading cause of cancer-related deaths and involves critical interactions between tumor cells and the microenvironment. Here we focused on elucidating the molecular hallmarks of tumor hypoxia that remains poorly defined. To fill this gap, we analyzed the genomic alterations and hypoxia score of 233 hypoxia-related genes of 6,343 individuals across 17 TCGA Pan-Cancer types. In addition, we analyzed a protein-protein interactome (PPi) network and the shortest paths from hypoxic proteins to metastasis. As results, mRNA high alteration was prevalent in all cancer types. Genomic alterations and hypoxia score presented a highest frequency in tumor stage 4 and positive metastasis status in all cancer types. The most significant signaling pathways were HIF-1, ErbB, PI3K-Akt, FoxO, mTOR, Ras and VEGF. The PPi network revealed a strong association among hypoxic proteins, cancer driver proteins and metastasis driver proteins. The analysis of shortest paths revealed 99 ways to spread metastasis signaling from hypoxic proteins. Additionally, we proposed 62 hypoxic genes strongly associated with metastasis and 27 of them with high amount of genomic alterations. Overall, tumor hypoxia may drive aggressive molecular features across cancer types. Hence, we identified potential biomarkers and therapeutic targets regulated by hypoxia that could be incorporated into strategies aimed at improving novel drug development and treating metastasis.

scholarly journals The Emerging Role of Suppressors of Cytokine Signaling (SOCS) in the Development and Progression of Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4000
Author(s):  
Esra’a Keewan ◽  
Ksenia Matlawska-Wasowska
Keyword(s):  
Intracellular Signaling ◽  
Cell Communication ◽  
Janus Kinase ◽  
Signaling Cascades ◽  
Cytokine Signaling ◽  
Surface Receptors ◽  
Wide Range ◽  
Stat Signaling ◽  
Leukemia Development

Cytokines are pleiotropic signaling molecules that execute an essential role in cell-to-cell communication through binding to cell surface receptors. Receptor binding activates intracellular signaling cascades in the target cell that bring about a wide range of cellular responses, including induction of cell proliferation, migration, differentiation, and apoptosis. The Janus kinase and transducers and activators of transcription (JAK/STAT) signaling pathways are activated upon cytokines and growth factors binding with their corresponding receptors. The SOCS family of proteins has emerged as a key regulator of cytokine signaling, and SOCS insufficiency leads to constitutive activation of JAK/STAT signaling and oncogenic transformation. Dysregulation of SOCS expression is linked to various solid tumors with invasive properties. However, the roles of SOCS in hematological malignancies, such as leukemia, are less clear. In this review, we discuss the recent advances pertaining to SOCS dysregulation in leukemia development and progression. We also highlight the roles of specific SOCS in immune cells within the tumor microenvironment and their possible involvement in anti-tumor immunity. Finally, we discuss the epigenetic, genetic, and post-transcriptional modifications of SOCS genes during tumorigenesis, with an emphasis on leukemia.

Artificial intelligence-based pathology for gastrointestinal and hepatobiliary cancers

Gut ◽  
2020 ◽  
pp. gutjnl-2020-322880 ◽  
Author(s):  
Julien Calderaro ◽  
Jakob Nikolas Kather
Keyword(s):  
Artificial Intelligence ◽  
Liver Cancer ◽  
Genetic Alterations ◽  
Clinical Implications ◽  
Complex Information ◽  
Wide Range ◽  
Depth Analysis ◽  
Cancer Types ◽  
Cancer Tissues ◽  
Very High

Artificial intelligence (AI) can extract complex information from visual data. Histopathology images of gastrointestinal (GI) and liver cancer contain a very high amount of information which human observers can only partially make sense of. Complementing human observers, AI allows an in-depth analysis of digitised histological slides of GI and liver cancer and offers a wide range of clinically relevant applications. First, AI can automatically detect tumour tissue, easing the exponentially increasing workload on pathologists. In addition, and possibly exceeding pathologist’s capacities, AI can capture prognostically relevant tissue features and thus predict clinical outcome across GI and liver cancer types. Finally, AI has demonstrated its capacity to infer molecular and genetic alterations of cancer tissues from histological digital slides. These are likely only the first of many AI applications that will have important clinical implications. Thus, pathologists and clinicians alike should be aware of the principles of AI-based pathology and its ability to solve clinically relevant problems, along with its limitations and biases.

scholarly journals Role of the JAK/STAT Pathway in Cervical Cancer: Its Relationship with HPV E6/E7 Oncoproteins

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2297
Author(s):  
Adriana Gutiérrez-Hoya ◽  
Isabel Soto-Cruz
Keyword(s):  
Cervical Cancer ◽  
Cancer Progression ◽  
Critical Role ◽  
Janus Kinase ◽  
Tumor Cell Death ◽  
Cellular Mechanisms ◽  
Poor Overall Survival ◽  
Stat Proteins ◽  
Stat Signaling ◽  
Stat Pathway

The janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is associated with the regulation of essential cellular mechanisms, such as proliferation, invasion, survival, inflammation, and immunity. Aberrant JAK/STAT signaling contributes to cancer progression and metastatic development. STAT proteins play an essential role in the development of cervical cancer, and the inhibition of the JAK/STAT pathway may be essential for enhancing tumor cell death. Persistent activation of different STATs is present in a variety of cancers, including cervical cancer, and their overactivation may be associated with a poor prognosis and poor overall survival. The oncoproteins E6 and E7 play a critical role in the progression of cervical cancer and may mediate the activation of the JAK/STAT pathway. Inhibition of STAT proteins appears to show promise for establishing new targets in cancer treatment. The present review summarizes the knowledge about the participation of the different components of the JAK/STAT pathway and the participation of the human papillomavirus (HPV) associated with the process of cellular malignancy.

scholarly journals The JAK/STAT signaling pathway: from bench to clinic

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Xiaoyi Hu ◽  
Jing li ◽  
Maorong Fu ◽  
Xia Zhao ◽  
Wei Wang
Keyword(s):  
Signaling Pathway ◽  
Current Knowledge ◽  
Janus Kinase ◽  
Signal Transducer ◽  
Quarter Century ◽  
Cellular Processes ◽  
Stat Signaling ◽  
Cancer And Inflammation ◽  
Stat Pathway

AbstractThe Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway was discovered more than a quarter-century ago. As a fulcrum of many vital cellular processes, the JAK/STAT pathway constitutes a rapid membrane-to-nucleus signaling module and induces the expression of various critical mediators of cancer and inflammation. Growing evidence suggests that dysregulation of the JAK/STAT pathway is associated with various cancers and autoimmune diseases. In this review, we discuss the current knowledge about the composition, activation, and regulation of the JAK/STAT pathway. Moreover, we highlight the role of the JAK/STAT pathway and its inhibitors in various diseases.

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