Biology subjects

Liang, W.

Publications and source records attributed to Liang, W..

7 recordsLinked to original sources

bioRxiv2018

Multi-scale modeling reveals angiogenesis-induced drug resistance in brain tumor and predicts a synergistic drug combination targeting EGFR and VEGFR pathways

Experimental studies have demonstrated that both the extracellular vasculature, microenvironment and intracellualr molecular network (e.g. epidermal growth factor receptor (EGFR) signaling pathways) are essentially important for brain tumor growth. Some drugs have been developed to inhibit the EGFR signaling pathways. However, how does angiogenesis affect the response of tumor cells to the drug treatment has rarely been mechanistically studied. Therefore, a multiscale model is required to investigate such complex biological systems that contain interactions and feedbacks among multi-levels. In this study, we developed a single cell-based multi-scale spatio-temporal model to simulate more realistic vascular tumor growth and drug response, based on VEGFR signaling pathways, EGFR signaling pathway and cell cycle as well as several microenvironmental factors that determine cell fate switches in a temporal and spatial context. The simulation reconstructed an evolving profile of vascular tumor growth, demonstrating the dynamic interplay between angiogenesis and various types of tumor cells (e.g., migrating, proliferating, apoptosis and quiescent cells). Moreover, we revealed the critical role of angiogenesis in the acquired drug resistance. We further investigated the optimal timing of combing VEGFR inhibition with EGFR inhibition and predicted that the drug combination targeting both EGFR pathway and VEGFR pathway has a synergistic effect. The experimental data validated the prediction of drug synergy, confirming the effectiveness of our model. The developed multiscale model explored mechanistic and functional mechanisms of angiogenesis underlying tumor growth and drug resistance, which advances our understanding of novel mechanisms of drug resistance and provides implications for designing more effective cancer therapies.\n\nAuthor summaryMany targeted therapies have been designed to treat malignant tumors including gliomas, but the clinical effectiveness of these therapies are limited due to the emergence of drug resistance during cancer therapeutics. The mechanisms underlying cancer drug resistance have not been fully understood until now, which restricts the rational designing of robust and effective therapeutics. Increasing number of experimental studies have indicated that angiogenesis plays important role s in influencing the effect of drug treatment. However, how does angiogenesis affect the response of tumor cells to the drug treatment has rarely been mechanistically studied. In this study we developed a single cell-based multi-scale spatio-temporal model to investigate the role of angiogenesis in drug response of brain tumors. The model demonstrated dual roles of angiogenesis in drug treatment of brain tumors and revealed a novel mechanism of angiogenesis-induced drug resistance. Moreover, the model predicted a synergistic drug combination targeting both EGFR and VEGFR pathways with optimal combination timing. This study has been dedicated to elucidate mechanistic and functional mechanisms of angiogenesis underlying tumor growth and drug resistance, providing implications for designing more effective drug combination therapies.

systems biology↗

bioRxiv2018

How do wind speed, release height, seed morphology interact to determine seed dispersal trajectory of Calligonum (Polygonaceae) species

How seed dispersal trajectory shifts with abiotic and biotic factors and what is the relationship between seed dispersal distance and dispersal trajectory are remain unclear. We used wind tunnel and video camera to track the seed dispersal trajectory of 7 Calligonum species with different appendages under the different wind speeds and the release heights. Dispersal trajectories and distances were determined by video analysis and spatial coordinate transformation. Based on perspective principle, 4 modes of trajectories were determined. Wind speed, seed mass and release height were the key factors determining seed dispersal trajectory modes. Release height and wind speed tended to have the strongest explanatory power on seeds with bristles and wings, respectively. Different trajectory modes lead to different dispersal distance, while the same dispersal distance can be the result of different trajectory modes. The proportion of species trajectory modes formed its trajectory spectrum. Wind speed tends to have strong influence on light and low-wind-loading seeds, release height tends to have that on heavy and high-wind-loading seeds. Species with high proportion of horizontal projectile and projectile have high dispersal capacity, vice versa. Therefore, trajectory spectrum of a species reveals its primary dispersal strategies and evolutionary consequences.

ecology↗

bioRxiv2018

Constant conflict between Gypsy LTR retrotransposons and CHH methylation within a stress-adapted mangrove genome

SummaryO_LIEvolutionary dynamics of the conflict between transposable elements (TEs) and their host genome remain elusive. This conflict would be intense in stress-adapted plants as stress can often reactivate TEs. Mangroves reduce TE load convergently in their adaptation to intertidal environments and thus provide a unique opportunity to address the host-TE conflict and its interaction with stress adaptation.\nC_LIO_LIUsing the mangrove Rhizophora apiculata as a model, we investigated methylation and short interfering RNA (siRNA) targeting patterns in relation to the abundance and age of long terminal repeat (LTR) retrotransposons. We also examined LTR retrotransposons distance to genes, impact on neighboring gene expression, and population frequencies.\nC_LIO_LIWe found differential accumulation among classes of LTR retrotransposons despite high overall methylation levels. This can be attributed to 24-nt siRNA-mediated CHH methylation preferentially targeting Gypsy elements, particularly in their LTR regions. Old Gypsy elements possess unusually abundant siRNAs which show cross-mapping to young copies. Gypsy elements appear to be closer to genes and under stronger purifying selection than other classes.\nC_LIO_LIOur results suggest a continuous host-TE battle masked by the TE load reduction in R. apiculata. This conflict may enable mangroves like R. apiculata to maintain genetic diversity and thus evolutionary potential during stress adaptation.\nC_LI

evolutionary biology↗

bioRxiv2018

Knockdown of GAS5 restores ox-LDL-induced impaired autophagy flux via upregulating miR-26a in human endothelial cells

BackgroundOxidized low-density lipoprotein (ox-LDL)-induced endothelial cell (EC) injury and autophagy dysfunction play a vital role in the development of atherosclerosis. LncRNAs have been identified to participate in the regulation of pathogenesis of atherosclerosis. However, it remains largely undefined whether growth-arrest specific transcript 5 (GAS5) could influence ox-LDL-induced autophagy dysfunction in ECs.\n\nMethodsThe expressions of GAS5 and miR-26a in the plasma samples of patients with atherosclerosis and ox-LDL-treated human aortic endothelial cells (HAECs) were detected by qRT-PCR. Luciferase reporter assay, RNA immunoprecipitation (RIP), and RNA pull down were performed to validate whether GAS5 could directly interact with miR-26a. The effects of ox-LDL, GAS5 or combined with miR-26a on apoptosis and autophagy were evaluated by flow cytometry analysis and western blot, respectively.\n\nResultsGAS5 expression was upregulated and miR-26a was downregulated in the plasma samples of patients with atherosclerosis and ox-LDL-treated HAECs. There was reciprocal inhibition between GAS5 and miR-26a expressions in ox-LDL-treated HAECs. We further demonstrated that GAS5 directly interacted with miR-26a in ox-LDL-treated HAECs. Additionally, ox-LDL administration induced apoptosis and impaired autophagy flux in HAECs. Rescue experiments demonstrated that GAS5 knockdown restored ox-LDL-induced impaired autophagy flux by upregulating miR-26a in HAECs.\n\nConclusionKnockdown of GAS5 restores ox-LDL-induced impaired autophagy flux via upregulating miR-26a in human endothelial cells, revealing a novel regulatory mechanism for ox-LDL-induced impaired autophagy flux in ECs through ceRNA crosstalk.

biochemistry↗

bioRxiv2018

Circular RNA expression and regulatory network prediction in posterior cingulate astrocytes in elderly subjects

BackgroundCircular RNAs (circRNAs) are a novel class of endogenous, non-coding RNAs that form covalently closed continuous loops and are both highly conserved and abundant in the mammalian brain. A role for circRNAs in sponging microRNAs (miRNAs) has been proposed, but the circRNA-miRNA-mRNA interaction networks in human brain cells have not been defined. Therefore, we identified circRNAs in RNA sequencing data previously generated from astrocytes microdissected from the posterior cingulate (PC) of Alzheimers disease (AD) patients (N=10) and healthy elderly controls (N=10) using four circRNA prediction algorithms - CIRI, CIRCexplorer, find_circ and KNIFE.\n\nResultsOverall, utilizing these four tools, we identified a union of 4,438 unique circRNAs across all samples, of which 70.3% were derived from exonic regions. Notably, the widely reported CDR1as circRNA was detected in all samples across both groups by find_circ. Given the putative miRNA regulatory function of circRNAs, we identified potential miRNA targets of circRNAs, and further, delineated circRNA-miRNA-mRNA networks using in silico methods. Pathway analysis of the genes regulated by these miRNAs identified significantly enriched immune response pathways, which is consistent with the known function of astrocytes as immune sensors in the brain.\n\nConclusionsIn this study, we performed circRNA detection on cell-specific transcriptomic data and identified potential circRNA-miRNA-mRNA regulatory networks in PC astrocytes. Given the known function of astrocytes in cerebral innate immunity and our identification of significantly enriched immune response pathways, the circRNAs we identified may be associated with such key functions. While we did not detect recurrent differentially expressed circRNAs in the context of healthy controls or Alzheimers, we report for the first time circRNAs and their potential regulatory impact in a cell-specific and region-specific manner in aged subjects. These predicted regulatory network and pathway analyses may help provide new insights into transcriptional regulation in the brain.

neuroscience↗

bioRxiv2017

Characterization of a Novel Model of Overuse-Induced Calcific Achilles Tendinopathy in Mice: Contralateral Tendinopathy Following Unilateral Tenotomy

ObjectiveTo develop a simple but reproducible overuse induced animal model of Achilles tendinopathy in mice for better understanding the underlying mechanism and prevention of calcific Achilles tendinopathy.\n\nMethods80 C57/B6 mice (8-9 weeks old) were employed and randomly divided into control group and experimental group. Unilateral Achilles tenotomy was performed on the right hindlimb of experiment group. After 12 weeks, the onset of Achilles tedinopathy in the contralateral Achilles tendon was determined by radiological assessment, histological analysis, electron microscopy observation and biomechanical test.\n\nResultsThe onset of calcific Achilles tendinopathy in contralateral Achilles tendon was confirmed after 12 weeks unilateral tenotomy. The contralateral Achilles tendon of experimental group was characterized as hypercelluarity, neovascularization and fused collagen fiber disarrangement, compared to the control group. Importantly, intratendon endochondral ossification and calcaneus deformity was featured in contralateral Achilles tendon. Additionally, poor biomechanical properties in the contralateral Achilles tendon revealed the incidence of Achilles tedinopathy.\n\nConclusionWe hereby introduce a novel simple but reproducible spontaneous contralateral calcific Achilles tendinopathy model in mice, which represents the overuse conditions during the tendinopathy development in human-beings. It should be a useful tool to further study the underlying pathogenesis of calcific Achilles tendinopathy.

animal behavior and cognition↗

bioRxiv2017

Somatic inactivating PTPRJ mutations and dysregulated pathways identified in canine melanoma by integrated comparative genomic analysis

Canine malignant melanoma, a significant cause of mortality in domestic dogs, is a powerful comparative model for human melanoma, but little is known about its genetic etiology. We mapped the genomic landscape of canine melanoma through multi-platform analysis of 37 tumors (31 mucosal, 3 acral, 2 cutaneous, and 1 uveal) and 17 matching constitutional samples including long- and short-insert whole genome sequencing, RNA sequencing, array comparative genomic hybridization, single nucleotide polymorphism array, and targeted Sanger sequencing analyses. We identified novel predominantly truncating mutations in the putative tumor suppressor gene PTPRJ in 19% of cases. No BRAF mutations were detected, but activating RAS mutations (24% of cases) occurred in conserved hotspots in all cutaneous and acral and 13% of mucosal subtypes. MDM2 amplifications (24%) and TP53 mutations (19%) were mutually exclusive. Additional low-frequency recurrent alterations were observed amidst low point mutation rates, an absence of ultraviolet light mutational signatures, and an abundance of copy number and structural alterations. Mutations that modulate cell proliferation and cell cycle control were common and highlight therapeutic axes such as MEK and MDM2 inhibition. This mutational landscape resembles that seen in BRAF wild-type and sun-shielded human melanoma subtypes. Overall, these data inform biological comparisons between canine and human melanoma while suggesting actionable targets in both species.\n\nAUTHOR SUMMARYMelanoma, an aggressive cancer arising from transformed melanocytes, commonly occurs in pet dogs. Unlike human melanoma, which most often occurs in sun-exposed cutaneous skin, canine melanoma typically arises in sun-shielded oral mucosa. Clinical features of canine melanoma resemble those of human melanoma, particularly the less common sun-shielded human subtypes. However, whereas the genomic basis of diverse human melanoma subtypes is well understood, canine melanoma genomics remain poorly defined. Similarly, although diverse new treatments for human melanoma based on a biologic disease understanding have recently shown dramatic improvements in outcomes for these patients, treatments for canine melanoma are limited and outcomes remain universally poor. Detailing the genomic basis of canine melanoma thus provides untapped potential for improving the lives of pet dogs while also helping to establish canine melanoma as a comparative model system for informing human melanoma biology and treatment. In order to better define the genomic landscape of canine melanoma, we performed multi-platform characterization of 37 tumors. Our integrated analysis confirms that these tumors commonly contain mutations in canine orthologs of human cancer genes such as RAS, MDM2, and TP53 as well mutational patterns that share important similarities with human melanoma subtypes. We have also found a new putative cancer gene, PTPRJ, frequently mutated in canine melanoma. These data will guide additional biologic and therapeutic studies in canine melanoma while framing the utility of comparative studies of canine and human cancers more broadly.

cancer biology↗