Biology subjects

Wu, G.

Publications and source records attributed to Wu, G..

At least 91 records · Page 5Linked to original sources

bioRxiv2023

The brain's topographical organization shapes dynamic interaction patterns to support flexible behavior

Understanding how human cognition flexibly supports distinct forms of behavior is a key goal of neuroscience. Adaptive behavior relies on context-specific rules that vary across situations, as well as on stable knowledge gained from experience. However, the mechanisms that allow these influences to be appropriately balanced remain elusive. Here, we show that this cognitive flexibility is partly supported by the topographical organization of the cortex. The frontoparietal control network (FPCN) is located between regions implicated in top-down attention and memory-guided cognition. We hypothesized that the FPCN is topographically divided into discrete systems that support these distinct forms of behavior. These FPCN subsystems exhibit multiple anatomical and functional similarities to their neighboring systems (the dorsal attention network and default mode network respectively). This topographic architecture is also mirrored in the functional patterns that emerge in different situations: the FPCN subnetworks act as a unified system when long-term memory can support behavior, but they segregate into discrete units when working memory, rather than long term memory, is necessary for behavioral control. In this way, the topographic organization of brain function provides crucial insights into how the human cortex supports flexible behavior.

neuroscience↗

bioRxiv2023

Skeletal Muscle Phenotype-Specific Effects of ACVR1B and TGFBR1 Receptor Signalling on Muscle Transcriptome, Force generation and Metabolism

Transforming growth factor-{beta} (TGF-{beta}) signaling is associated with progressive skeletal muscle wasting and fibrosis, while double knockout of TGF-{beta} type I receptors Acvr1b and Tgfbr1 results in hypertrophy. Gaining insights in how myofibre-specific knockout of these receptors affects muscle transcriptome, strength and mitochondrial activity could aid in the development of therapeutic interventions to improve muscle function. Here, we show that 3 months of myofibre-specific knockout of both receptors (dKO) in mice induced a 1.6-fold increase in gastrocnemius medialis mass and a 1.3-fold increase in maximal force. Soleus muscle mass and maximal force both increased 1.2-fold in dKO mice. Muscle hypertrophy in dKO mice was accompanied by a proportional increase in succinate dehydrogenase enzyme activity. Single receptor knockout caused minor phenotypical alterations. Transcriptome analyses revealed that gastrocnemius medialis had 1811 and soleus had 295 differentially expressed genes, mainly related to muscle contraction, hypertrophy, filament organization and oxidative metabolism. Hgf and Sln genes were strongly upregulated in both muscles of dKO mice, while Sntb1 was downregulated. This in combination of transcriptional changes are associated with muscle hypertrophy and increased mitochondrial biosynthesis. Our study highlights that myofibre-specific interference with both TGF-{beta} type I receptors concurrently stimulates myofibre hypertrophy and mitochondrial activity.

physiology↗

bioRxiv2023

Interaction between host G3BP and viral nucleocapsid protein regulates SARS-CoV-2 replication

G3BP1/2 are paralogous proteins that promote stress granule formation in response to cellular stresses, including viral infection. G3BP1/2 are prominent interactors of the nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the functional consequences of the G3BP1-N interaction in the context of viral infection remain unclear. Here we used structural and biochemical analyses to define the residues required for G3BP1-N interaction, followed by structure-guided mutagenesis of G3BP1 and N to selectively and reciprocally disrupt their interaction. We found that mutation of F17 within the N protein led to selective loss of interaction with G3BP1 and consequent failure of the N protein to disrupt stress granule assembly. Introduction of SARS-CoV-2 bearing an F17A mutation resulted in a significant decrease in viral replication and pathogenesis in vivo, indicating that the G3BP1-N interaction promotes infection by suppressing the ability of G3BP1 to form stress granules.

cell biology↗

bioRxiv2023

Metabolic reprogramming of cancer cells by JMJD6-mediated pre-mRNA splicing is associated with therapeutic response to splicing inhibitor

Dysregulated pre-mRNA splicing and metabolism are two hallmarks of MYC-driven cancers. Pharmacological inhibition of both processes has been extensively investigated as potential therapeutic avenues in preclinical and clinical studies. However, how pre-mRNA splicing and metabolism are orchestrated in response to oncogenic stress and therapies is poorly understood. Here, we demonstrate that Jumonji Domain Containing 6, Arginine Demethylase and Lysine Hydroxylase, JMJD6, acts as a hub connecting splicing and metabolism in MYC-driven neuroblastoma. JMJD6 cooperates with MYC in cellular transformation by physically interacting with RNA binding proteins involved in pre-mRNA splicing and protein homeostasis. Notably, JMJD6 controls the alternative splicing of two isoforms of glutaminase (GLS), namely kidney-type glutaminase (KGA) and glutaminase C (GAC), which are rate-limiting enzymes of glutaminolysis in the central carbon metabolism in neuroblastoma. Further, we show that JMJD6 is correlated with the anti-cancer activity of indisulam, a "molecular glue" that degrades splicing factor RBM39, which complexes with JMJD6. The indisulam-mediated cancer cell killing is at least partly dependent on the glutamine-related metabolic pathway mediated by JMJD6. Our findings reveal a cancer-promoting metabolic program is associated with alternative pre-mRNA splicing through JMJD6, providing a rationale to target JMJD6 as a therapeutic avenue for treating MYC-driven cancers.

cancer biology↗

bioRxiv2023

Cotyledon Peeling Method for Passion Fruit Protoplasts: a versatile cell system for transient gene expression in passion fruit (Passiflora edulis)

Passion fruit (Passiflora edulis) is a perennial evergreen vine that grows mainly in tropical and subtropical regions due to its nutritional, medicinal and ornamental values. However, the molecular biology study of passion fruit is extremely hindered by the lack of an easy and efficient method for transformation. The protoplast transformation system plays a vital role in plant regeneration, gene function analysis and genome editing. Here, we present a new method ( Cotyledon Peeling Method) for simple and efficient passion fruit protoplast isolation using cotyledon as the source tissue. A high yield (2.3 x 107 protoplasts per gram of fresh tissues) and viability (76%) of protoplasts were obtained upon incubation in the enzyme solution [1% (w/v) cellulase R10, 0.25% (w/v) macerozyme R10, 0.4 M mannitol, 10 mM CaCl2, 20 mM KCl, 20 mM MES and 0.1% (w/v) BSA, pH 5.7] for 2 hours. In addition, we achieved high transfection efficiency of 83% via the polyethylene glycol (PEG)-mediated transformation with a green fluorescent protein (GFP)-tagged plasmid upon optimization. The crucial factors affecting transformation efficiency were optimized as follows: 3 g of plasmid DNA, 5 min transfection time, PEG concentration at 40% and protoplast density of 100 x 104 cells/ml. Furthermore, the established protoplast system was successfully applied for subcellular localization analysis of multiple fluorescent organelle markers and protein-protein interaction study. Taken together, we report a simple and efficient passion fruit protoplast isolation and transformation system, and demonstrate its usage in transient gene expression for the first time in passion fruit. The protoplast system would provide essential support for various passion fruit biology studies, including genome editing, gene function analysis and whole plant regeneration.

plant biology↗

bioRxiv2023

The TRIP6/LATS1 complex constitutes the tension sensor of α-catenin/vinculin at both bicellular and tricellular junctions

Cell-cell mechanotransduction regulates tissue development and homeostasis. -catenin, the core component of adherens junctions, functions as a tension sensor and transducer by recruiting vinculin and transducing the signals to influence cell behaviors. However, little is known about the components, distributions, and dynamics of the -catenin based tension sensors at the cell junctions. Here, we uncovered the TRIP6/LATS1 complex locates at the tension sites where -catenin/vinculin is at both the bicellular junctions (BCJs) and tricellular junctions (TCJs). Vinculin/TRIP6/LATS1 are prone to form as puncta in the cytoplasm without -catenin participation. Furthermore, the tension sensing complex distributed stronger at TCJs and exhibited a discontinuously button-like pattern on BCJs. The -catenin/vinculin BiFC-based mechanosensor further proved the discontinuous distribution of the tension at BCJs, and was more motile than the TCJs. In summary, our study revealed that TRIP6 and LATS1 are novel compositions of the tension sensor, together with the core complex of -catenin/vinculin, at both the BCJs and TCJs. This work gives insights and improvements in exploring the molecular mechanism that mediates cell-cell mechanotransduction at cell junctions.

cell biology↗

bioRxiv2023

Illuminating Dark Proteins using Reactome Pathways

Limited knowledge about a substantial portion of protein coding genes, known as "dark" proteins, hinders our understanding of their functions and potential therapeutic applications. To address this, we leveraged Reactome, the most comprehensive, open source, open-access pathway knowledgebase, to contextualize dark proteins within biological pathways. By integrating multiple resources and employing a random forest classifier trained on 106 protein/gene pairwise features, we predicted functional interactions between dark proteins and Reactome-annotated proteins. We then developed three scores to measure the interactions between dark proteins and Reactome pathways, utilizing enrichment analysis and fuzzy logic simulations. Correlation analysis of these scores with an independent single-cell RNA sequencing dataset provided supporting evidence for this approach. Furthermore, systematic natural language processing (NLP) analysis of over 22 million PubMed abstracts and manual checking of the literature associated with 20 randomly selected dark proteins reinforced the predicted interactions between proteins and pathways. To enhance the visualization and exploration of dark proteins within Reactome pathways, we developed the Reactome IDG portal, deployed at https://idg.reactome.org, a web application featuring tissue-specific protein and gene expression overlay, as well as drug interactions. Our integrated computational approach, together with the user-friendly web platform, offers a valuable resource for uncovering potential biological functions and therapeutic implications of dark proteins.

bioinformatics↗

bioRxiv2023

System Neglect and the Neurocomputational Substrates for Over- and Underreactions to Change

AO_SCPLOWBSTRACTC_SCPLOWThe world constantly changes, with the underlying state of the world shifting from one regime to another. The ability to detect a regime shift, such as the onset of a pandemic or the end of a recession, significantly impacts individual decisions as well as governmental policies. However, determining whether a regime has changed is usually not obvious, as signals are noisy and reflective of the volatility of the environment. We designed an fMRI paradigm that examines a stylized regime-shift detection task. Human participants showed systematic over- and underreaction: Overreaction was most commonly seen when signals were noisy but when environments were stable and change is possible but unlikely. By contrast, underreaction was observed when signals were precise but when environments were unstable and hence change was more likely. These behavioral signatures are consistent with the system-neglect computational hypothesis, which posits that sensitivity or lack thereof to system parameters (noise and volatility) is central to these behavioral biases. Guided by this computational framework, we found that individual subjects sensitivity to system parameters were represented by two distinct brain networks. Whereas a frontoparietal network selectively represented individuals sensitivity to signal noise but not environment volatility, the ventromedial prefrontal cortex (vmPFC) showed the opposite pattern. Further, these two networks were involved in different aspects of regime-shift computations: while vmPFC correlated with subjects beliefs about change, the frontoparietal network represented the strength of evidence in favor of regime shifts. Together, these results suggest that regime-shift detection recruits belief-updating and evidence-evaluation networks and that under- and overreactions arise from how sensitive these networks are to the system parameters. SO_SCPLOWIGNIFICANCEC_SCPLOW SO_SCPLOWTATEMENTC_SCPLOWJudging whether the world has changed, from the onset of a market boom to the end of a pandemic, is ubiquitous. The ability to detect regime shifts not only impacts individual decisions but also governmental policies. However, these judgments are hard to make because the signals we receive are noisy and reflective of the volatility of the environment. We find that people overreact to changes when they receive noisy signals in stable environments, but underreact when facing precise signals in unstable environments. Under- and overreactions can be read out by distinct brain networks according to their sensitivity in responding to different environmental parameters that impact regime changes. This suggests that parameter selectivity at the network level guides regime-shift detection.

neuroscience↗

bioRxiv2023

Guild-level response of the gut microbiota to isocaloric time-restricted feeding in high-fat diet-fed mice

Time-restricted feeding (TRF) during the active phase protects against high-fat diet (HFD)-induced obesity, and its impact on gut microbiota has been previously investigated using bacterial taxa as functional units. However, in the gut ecosystem, bacteria from different taxonomic backgrounds form coherent functional groups called guilds, whose members exhibit co-abundant behavior. Thirty-five co-abundance groups (CAGs), clustered from 297 prevalent amplicon sequence variants (ASVs), showed greater concordance with beta-diversity plots based on all 1131 ASVs than the 130 classifiable genera, leading to a significantly improved preservation of community-level information. TRF-enriched CAGs positively correlated with metabolic improvement, while TRF-reduced CAGs negatively correlated. TRF restored the diurnal rhythm of most of these key CAGs. Novel ASVs, unclassifiable at the genus level, were identified in these key CAGs. Overall, this suggests that the key bacterial guilds may mediate the beneficial metabolic effects of TRF through the restoration of diurnal oscillation.

microbiology↗

bioRxiv2023

Subtype-specific circadian clock dysregulation modulates breast cancer biology, invasiveness, and prognosis.

Studies in shift workers and model organisms link circadian disruption to breast cancer. However, molecular rhythms in non-cancerous and cancerous human breast tissues are largely unknown. We reconstructed rhythms informatically, integrating locally collected, time-stamped biopsies with public datasets. For non-cancerous tissue, the inferred order of core-circadian genes matches established physiology. Inflammatory, epithelial-mesenchymal transition (EMT), and estrogen responsiveness pathways show circadian modulation. Among tumors, clock correlation analysis demonstrates subtype-specific changes in circadian organization. Luminal A organoids and informatic ordering of Luminal A samples exhibit continued, albeit disrupted rhythms. However, CYCLOPS magnitude, a measure of global rhythm strength, varied widely among Luminal A samples. Cycling of EMT pathway genes was markedly increased in high-magnitude Luminal A tumors. Patients with high-magnitude tumors had reduced 5-year survival. Correspondingly, 3D Luminal A cultures show reduced invasion following molecular clock disruption. This study links subtype-specific circadian disruption in breast cancer to EMT, metastatic potential, and prognosis.

cancer biology↗

bioRxiv2023

Compensation or preservation? Different roles of functional lateralization in speech perception in older non-musicians and musicians

Musical training can offset age-related decline of speech perception in noisy environments. However, whether functional compensation or functional preservation the older musicians adopt to counteract the adverse effects of aging is unclear yet, so do older non-musicians. Here, we employed the fundamental brain organization feature named functional lateralization, and calculated network-based lateralization indices (LIs) of resting-state functional connectivity (FC) in 23 older musicians (OM), 23 older non-musicians (ONM), and 24 young non-musicians (YNM). OM outperformed ONM and almost equalized YNM in speech-in-noise/speech tasks. In parallel, ONM exhibited reduced lateralization than YNM in LI of intrahemispheric FC (LI_intra) in cingulo-opercular network (CON) and interhemispheric heterotopic FC (LI_he) in language network (LAN). Moreover, OM showed higher neural alignment to YNM (i.e., similar lateralization pattern) than ONM in LI_intra in CON, LAN, frontoparietal network (FPN) and default mode network (DMN) and LI_he in DMN. These findings suggest that musical training contributes to the preservation of youth-like lateralization in older adults. Furthermore, stronger left-lateralized and lower alignment-to-young of LI_intra in somatomotor network (SMN) and dorsal attention network (DAN) and LI_he in DMN correlated with better speech performance in ONM. In contrast, stronger right-lateralized LI_intra in FPN and DAN and higher alignment-to-young of LI_he in LAN correlated with better performance in OM. Thus, functional preservation and compensation of lateralization may play different roles in speech perception in noise for the elderly with and without musical expertise, respectively. Our findings provide insight into successful aging theories from the unique perspective of functional lateralization and speech perception. Significance statementAs a positive lifestyle which contributes to neural resource enrichment, musical training experience may mitigate age-related decline in speech perception in noise through both functional compensation and preservation. What is unknown is whether older musicians rely more on one of these mechanisms, and how is it different from older non-musicians. From a unique perspective of functional lateralization, we found that high-performing older musicians showed stronger preservation of youth-like lateralization with a more right-lateralized pattern whereas high-performing older non-musicians were associated with stronger scaffolding of compensatory networks with a more left-lateralized pattern. Our findings suggest that older musicians and non-musicians exhibit different coping strategies in terms of functional lateralization against aging, which would largely enrich aging theories and inspire training intervention.

neuroscience↗

bioRxiv2023

High-altitude hypoxia exposure inhibits erythrophagocytosis by inducing macrophage ferroptosis in the spleen

High-altitude polycythemia (HAPC) is a chronic condition prevalent in individuals residing at high altitudes (HA), characterized by an augmented production of red blood cells (RBCs) due to hypoxic conditions. Despite its prevalence, the pathophysiological basis and molecular mechanisms driving HAPC remain largely unelucidated. In our study, we utilized a mouse model exposed to hypobaric hypoxia (HH), replicating the environmental conditions experienced at 6000 m above sea level, coupled with in vitro analysis of primary splenic macrophages under 1% O2 to investigate these mechanisms. Our findings revealed that HH exposure significantly stimulates erythropoiesis, leading to erythrocytosis. This was accompanied by a notable sequence of splenic changes, initially characterized by splenic contraction, which subsequently progressed to splenomegaly over 14 days. A key observation was the impairment on the capacity of spleen to process RBCs, primarily attributed to a reduction in splenic macrophages located in the red pulp. Extended HH treatment over 7 and 14 days precipitated increased iron mobilization and the onset of ferroptosis within the spleen. This was evidenced by altered expression levels of iron metabolism and ferroptosis-related proteins, paralleling gene expression patterns observed in human peripheral blood mononuclear cells. Single-cell sequencing of splenic tissue post-HH exposure demonstrated a marked decrease in macrophage populations after 7 days. Our study further disclosed a significant increase in RBCs retention in the spleen following HH exposure, likely a consequence of diminished red pulp macrophages (RPMs) and erythrophagocytosis. This hypothesis was corroborated through comprehensive analyses involving flow cytometry, histological staining, and immunostaining, which collectively provided a detailed understanding of RBCs dynamics under HH conditions. In vitro analyses substantiated the decline in primary splenic macrophages and induction of ferroptosis under hypoxic treatment, effects that were relieved by pre-treatment with the ferroptosis inhibitor ferrostatin-1. Collectively, our data suggest that HH exposure initiates splenic ferroptosis, leading primarily to a decrease in RPMs. This decrease potentially impacts erythrophagocytosis, contributing to increased RBCs retention and subsequent splenomegaly. Such changes could potentially foster continuous RBCs production and accelerate the progress of HAPC. In conclusion, our study highlights the important role of the spleen and splenic macrophages in the pathogenesis of HAPC, providing crucial insights into the disease progression and potential therapeutic targets.

physiology↗

bioRxiv2023

Free ferrous ions sustain activity of mammalian stearoyl-CoA desaturase-1

Mammalian stearoyl-CoA desaturase-1 (SCD1) introduces a double-bond to a saturated long-chain fatty acid and the reaction is catalyzed by a diiron center, which is well-coordinated by conserved histidine residues and is thought to remain with enzyme. However, we find that SCD1 progressively loses its activity during catalysis and becomes fully inactive after nine turnovers. Further studies show that the inactivation of SCD1 is due to the loss of an iron (Fe) ion in the diiron center, and that the addition of free ferrous ions (Fe2+) sustains the enzymatic activity. Using SCD1 labeled with Fe isotope, we further show that free Fe2+ is incorporated into the diiron center only during catalysis. We also discover that the diiron center in SCD1 has prominent electron paramagnetic resonance signals in its diferric state, indicative of distinct coupling between the two ferric ions. These results reveal that the diiron center in SCD1 is structurally dynamic during catalysis and that labile Fe2+ in cells could regulate SCD1 activity, and hence lipid metabolism.

biochemistry↗

bioRxiv2023

The landscape of cancer rewired GPCR signaling axes

We explored the dysregulation of GPCR ligand signaling systems in cancer transcriptomics datasets to uncover new therapeutics opportunities in oncology. We derived an interaction network of receptors with ligands and their biosynthetic enzymes, which revealed that multiple GPCRs are differentially regulated together with their upstream partners across cancer subtypes. We showed that biosynthetic pathway enrichment from enzyme expression recapitulated pathway activity signatures from metabolomics datasets, providing valuable surrogate information for GPCRs responding to organic ligands. We found that several GPCRs signaling components were significantly associated with patient survival in a cancer type-specific fashion. The expression of both receptor-ligand (or enzymes) partners improved patient stratification, suggesting a synergistic role for the activation of GPCR networks in modulating cancer phenotypes. Remarkably, we identified many such axes across several cancer molecular subtypes, including many pairs involving receptor- biosynthetic enzymes for neurotransmitters. We found that GPCRs from these actionable axes, including e.g., muscarinic, adenosine, 5-hydroxytryptamine and chemokine receptors, are the targets of multiple drugs displaying anti-growth effects in large-scale, cancer cell drug screens. We have made the results generated in this study freely available through a webapp (gpcrcanceraxes.bioinfolab.sns.it). SignificanceComprehensive analysis of GPCR extracellular network in cancer transcriptomics datasets reveals signaling axes associated to patient survival, whose targeting is associated with growth inhibition in cancer cell lines drug sensitivity assays.

bioinformatics↗

bioRxiv2023

Connectional Hierarchy in Human Brain Revealed by Individual Variability of Functional Network Edges

The human cerebral cortex exhibits intricate interareal functional synchronization at the macroscale, with substantial individual variability in these functional connections. However, the spatial organization of functional connectivity (FC) variability across the human connectome edges and its significance in cognitive development remain unclear. Here, we identified a connectional axis in the edge-level FC variability. The variability declined continuously along this axis from within-network to between-network connections, and from the edges linking association networks to those linking the sensorimotor and association networks. This connectional axis of functional variability is associated with spatial pattern of structural connectivity variability. Moreover, the connectional variability axis evolves in youth with an increasing flatter axis slope. We also observed that the slope of connectional variability axis was positively related to the performance in the higher-order cognition. Together, our results reveal a connectional axis in functional variability that is linked with structural connectome variability, refines during development, and is relevant to cognition. Significance StatementUnderstanding the spatial organization of inter-individual variability in functional connectivity across the human connectome can offer insights into which connections are most susceptible to insults and interventions. We identify a stable axis on functional connectome along which connectivity variability continuously varies, aligning with structural connectivity variability. We find that the pattern of this axis evolves during development, marked by a decrease in functional connectivity variability among association connections. Moreover, the variability axis is associated with individual differences in higher-order cognitions, driven by increased variability in higher-order association connections linked to enhanced cognitive performance. These findings highlight the importance of connectivity-specific plasticity in understanding both typical and atypical cognitive development across diverse populations.

neuroscience↗

bioRxiv2023

Classification of dog breeds using convolutional neural network models and support vector machine

Convolutional neural network (CNN) has been widely used for fine-grained image classification, which has proven to be an effective approach for the classification and identification of specific species. For breed classification of dog, there are several proposed methods based on dog images, however, the highest accuracy rate for dogs (about 93%) is still below expectations compared to other animals or plants (more than 95% on birds and more than 97% on flowers). In this study, we used the Stanford Dog Dataset, combined image features from four CNN models, filtered the features using principal component analysis (PCA) and gray wolf optimization algorithm (GWO), and then classified the features with support vector machine (SVM). Eventually, the classification accuracy rate reached 95.24% for 120 breeds and 99.34% for 76 selected breeds, respectively, demonstrating a significant improvement over existing methods using the same Stanford Dog Dataset. It is expected that our proposed method will further serve as a fundamental framework for accurate classification of a wider range of species.

bioinformatics↗

bioRxiv2022

Three-dimensional molecular architecture of mouse organogenesis

Mammalian embryos have sophisticated cell organizations that are orchestrated by molecular regulation at cellular and tissue level. It has recently been appreciated that the cells that make up the animal body themselves harbor significant heterogeneity in the context of both cellular and particularly spatial dimension. However, current spatial transcriptomics profiling of embryonic tissues either lack three-dimensional representation or are restricted to limited depth and organs. Here, we reported a holistic spatial transcriptome atlas of all major organs at embryonic day 13.5 of mouse embryo and delineated a 3D rendering of the molecular regulation of embryonic patterning. By integrating with corresponding single-cell transcriptome data, the spatial organogenesis atlas provides rich molecular annotation of the dynamic organ nature, spatial cellular interaction, embryonic axes and divergence of cell fates underlying mammalian development, which would pave the way for precise organ-engineering and stem-cell based regenerative medicine.

developmental biology↗

bioRxiv2022

The Circadian Clock is Disrupted in Pancreatic Cancer

Disruption of the circadian clock is linked to cancer development and progression. Establishing this connection has proven beneficial for understanding cancer pathogenesis, determining prognosis, and uncovering novel therapeutic targets. However, barriers to characterizing the circadian clock in human pancreas and human pancreatic cancer - one of the deadliest malignancies - have hindered an appreciation of its role in this cancer. Here, we employed normalized coefficient of variation (nCV) and clock correlation analysis in human population-level data to determine the functioning of the circadian clock in pancreas cancer and adjacent normal tissue. We found a substantially attenuated clock in the pancreatic cancer tissue. Then we exploited our existing mouse pancreatic transcriptome data to perform an analysis of the human normal and pancreas cancer samples using a machine learning method, cyclic ordering by periodic structure (CYCLOPS). Through CYCLOPS ordering, we confirmed the nCV and clock correlation findings of an intact circadian clock in normal pancreas with robust cycling of several core clock genes. However, in pancreas cancer, there was a loss of rhythmicity of many core clock genes with an inability to effectively order the cancer samples, providing substantive evidence of a dysregulated clock. The implications of clock disruption were further assessed with a Bmal1 knockout pancreas cancer model, which revealed that an arrhythmic clock caused accelerated cancer growth and worse survival, accompanied by chemoresistance and enrichment of key cancer-related pathways. These findings provide strong evidence for clock disruption in human pancreas cancer and demonstrate a link between circadian disruption and pancreas cancer progression. Author SummaryThe circadian clock is a regulator of human homeostasis. Dysfunction of the clock can lead to the development of diseases, including cancer. Although several cancers have been shown to have a dysfunctional clock which may alter prognosis or change treatment, this has been suggested but not demonstrated in pancreatic cancer. Investigation of this link is important because pancreatic cancer is highly lethal with few effective treatment options. Here we use recently pioneered bioinformatics approaches to assess clock functionality in human pancreatic cancer specimens, where we demonstrate that the clock is dysfunctional relative to normal pancreatic tissue. We then knocked out the core clock gene, Bmal1, in pancreatic cancer cells, which led to faster tumor growth and worse survival in mice and enhanced chemotherapeutic resistance to standard chemotherapy agents used in the treatment of pancreatic cancer. Collectively, our findings establish human pancreatic cancer as having clock dysfunction and clock dysfunction causing a more aggressive cancer.

cancer biology↗