Biology subjects

Cheng, F.

Publications and source records attributed to Cheng, F..

82 records · Page 5Linked to original sources

bioRxiv2020

Branched chain amino acid aminotransferase 2 Regulates Ferroptotic Cell Death in Cancer Cells

Ferroptosis has been implicated as a tumor-suppressor function for cancer therapy. Recently the sensitivity to ferroptosis was tightly linked to numerous biological processes, including metabolism of amino acid. Here, using a high-throughput CRISPR/Cas9 based genetic screen in HepG2 cells to search for metabolic proteins inhibiting ferroptosis, we identified branched chain amino acid aminotransferase 2 (BCAT2) as a novel suppressor of ferroptosis. Mechanistically, ferroptosis inducers (erastin, sorafenib and sulfasalazine) activated AMPK/SREBP1 signaling pathway through ferritinophagy, which in turn inhibited BCAT2 transcription. We further confirmed that BCAT2 mediating the metabolism of sulfur amino acid, regulated intracellular glutamate level, whose activation by ectopic expression specifically antagonize system Xc- inhibition and protected liver and pancreatic cancer cells from ferroptosis in vitro and in vivo. Finally, our results demonstrate the synergistic effect of sorafenib and sulfasalazine in downregulating BCAT2 expression and dictating ferroptotic death, where BCAT2 can also be used to predict the responsiveness of cancer cells to ferroptosis-inducing therapies. Collectively, these findings identify a novel role of BCAT2 in ferroptosis, suggesting a potential therapeutic strategy for overcoming sorafenib resistance.

cancer biology↗

bioRxiv2020

Combined Treatment with Dopamine Receptor Antagonists and Radiation Creates a Metabolic Vulnerability in Mouse Models of Glioblastoma

BackgroundGlioblastoma is the deadliest brain tumor in adults and the standard-of-care consists of surgery followed by radiation and treatment with temozolomide. Overall survival times for patients suffering from glioblastoma are unacceptably low indicating an unmet need for novel treatment options. MethodsUsing patient-derived glioblastoma lines and mouse models of glioblastoma we test the effect of radiation and the dopamine receptor antagonist on glioblastoma self-renewal in vitro and survival in vivo. A possible resistance mechanism is investigated using RNA-Sequencing. ResultsTreatment of glioma cells with the dopamine receptor antagonist quetiapine reduced glioma cell self-renewal in vitro and combined treatment of mice with quetiapine and radiation prolonged the survival of glioma-bearing animals. The combined treatment induced the expression of genes involved in cholesterol biosynthesis. This rendered the tumors vulnerable to simultaneous treatment with atorvastatin and further significantly prolonged the survival of the animals. ConclusionsOur results indicate high efficacy of a triple combination of quetiapine, atorvastatin and radiation against glioblastoma without increasing the toxicity of radiation. With both drugs readily available for clinical use our study could be rapidly translated into a clinical trial.

neuroscience↗

bioRxiv2019

The Dopamine Receptor Antagonist TFP Prevents Phenotype Conversion and Improves Survival in Mouse Models of Glioblastoma

Glioblastoma (GBM) is the deadliest adult brain cancer and all patients ultimately succumb to the disease. Radiation therapy (RT) provides survival benefit of 6 months over surgery alone but these results have not improved in decades. We report that radiation induces a glioma-initiating cell phenotype and we have identified trifluoperazine (TFP) as a compound that interferes with this phenotype conversion. TFP caused loss of radiation-induced Nanog mRNA expression, activation of GSK3 with consecutive post-translational reduction in p-Akt, Sox2 and {beta}-catenin protein levels. TFP did not alter the intrinsic radiation sensitivity of glioma-initiating cells (GICs). Continuous treatment with TFP and a single dose of radiation reduced the number of GICs in vivo and prolonged survival in syngeneic and patient-derived orthotopic xenograft (PDOX) mouse models of GBM. Our findings suggest that combination of a dopamine receptor antagonist with radiation enhances the efficacy of RT in GBM by preventing radiation-induced phenotype conversion of radiosensitive non-GICs into treatment resistant, induced GICs. SignificanceGBM is the most common and most deadly adult brain cancer. The current standard-of-care is surgery followed by RT and temozolomide, which results in a median survival time of only 15 months. The efficacy of chemotherapies and targeted therapies in GBM is very limited because most of these drugs do not pass the blood-brain-barrier. Ultimately, all patients succumb to the disease. Our study describes radiation-induced cellular plasticity as a novel resistance mechanism in GBM. We identified a dopamine receptor antagonist as a readily available, FDA-approved drug known to penetrate the blood-brain-barrier which prevents phenotype conversion of glioma cells into glioma-initiating cells and prologs survival in mouse models of GBM, thus suggesting that it will improve the efficacy of RT without increasing toxicity.

neuroscience↗

bioRxiv2019

Vimentin provides the mechanical resilience required for amoeboid migration and protection of the nucleus.

Dendritic cells use amoeboid migration through constricted passages to reach the lymph nodes, and this homing function is crucial for immune responses. Amoeboid migration requires mechanical resilience, however, the underlying molecular mechanisms for this type of migration remain unknown. Because vimentin intermediate filaments (IFs) and microfilaments regulate adhesion-dependent migration in a bidirectional manner, we analyzed if they exert a similar control on amoeboid migration. Vimentin was required for cellular resilience, via a joint interaction between vimentin IFs and F-actin. Reduced actin mobility in the cell cortex of vimentin-reduced cells indicated that vimentin promotes Factin subunit exchange and dynamics. These mechano-dynamic alterations in vimentin-deficient dendritic cells impaired amoeboid migration in confined environments in vitro and blocked lymph node homing in mouse experiments in vivo. Correct nuclear positioning is important in confined amoeboid migration both to minimize resistance and to avoid DNA damage. Vimentin-deficiency also led to DNA double strand breaks in the compressed dendritic cells, pointing to a role of vimentin in nuclear positioning. Together, these observations show that vimentin IF-microfilament interactions provide both the specific mechano-dynamics required for dendritic cell migration and the protection the genome needs in compressed spaces.\n\nSummary statementVimentin -- in joint action with actin -- mediates the mechanical stiffness of cells required for amoeboid cell migration through confined spaces and protects the nucleus from DNA damage.

biophysics↗

bioRxiv2018

Seasonal diets overwhelm host species in shaping the gut microbiota of Yak and Tibetan sheep

Host genetics and environmental factors can both shaping composition of gut microbiota, yet which factors are more important is still under debating. Yak (Bos grunniens) and Tibetan sheep (Ovis aries) are very different from the size and genetics. Nomadic Tibetan people keep them as main livestock and feeding them with same grazing systems, which provide a good opportunity to study the effects of diet and host species on gut microbiome. We collected fecal samples from yaks and Tibetan sheeps at different seasons when they were feed with different diets. Illumina data showed that major bacterial phyla of both animals are Bacteroidetes and Firmicutes, which agree with the previous reports. And the season effect had a higher impact on the gut microbiota than that of host species, though the animals are taxonomically distinguished each other at subfamily level. Since that the animal grazing differently at different seasons, this study indicated that diet can trump the host genetics even at higher taxonomic level. This finding provides a cautionary note for the researchers to link host genetics to the composition and function of the gut microbiota.\n\nImportanceYak and Tibetan sheep are very different from the size and genetics (from different sub-family). Nomadic Tibetan people keep them as main livestock and feeding them with same grazing systems, which provide a good opportunity to study the effects of diet and host species on the gut microbiota. Results indicated that diet can trump the host genetics even at higher taxonomic level. This finding provides a cautionary note for the researchers to link host genetics to the composition and function of the gut microbiota.

ecology↗

bioRxiv2018

Multi-Center Study of Resectable Lung Lesions by Ultra-Deep Sequencing of Targeted Genes in Plasma Cell-Free DNA to Assess Nodule Malignancy and Detect Lung Cancers

BACKGROUNDEarly detection of lung cancer to allow curative treatment remains challenging. Cell-free circulating tumor DNA (ctDNA) analysis may aid in malignancy assessment and early cancer diagnosis of lung nodules found in screening imagery.\n\nMETHODSThe multi-center clinical study enrolled 192 patients with operable occupying lung diseases. Plasma ctDNA, white blood cell genomic DNA (gDNA) and tumor tissue gDNA of each patient were analyzed by ultra-deep sequencing to an average of 35,000X of the coding regions of 65 lung cancer-related genes.\n\nRESULTSThe cohort consists of a quarter of benign lung diseases and three quarters of cancer patients with all histopathology subtypes. 64% of the cancer patients is at Stage I. Gene mutations detection in tissue gDNA and plasma ctDNA results in a sensitivity of 91% and specificity of 88%. When ctDNA assay was used as the test, the sensitivity was 69% and specificity 96%. As for the lung cancer patients, the assay detected 63%, 83%, 94% and 100%, for Stage I, II, III and IV, respectively. In a linear discriminant analysis, combination of ctDNA, patient age and a panel of serum biomarkers boosted the overall sensitivity to 80% at a specificity of 99%. 29 out of the 65 genes harbored mutations in the lung cancer patients with the largest number found in TP53 (30% plasma and 62% tumor tissue samples) and EGFR (20% and 40%, respectively).\n\nCONCLUSIONPlasma ctDNA was analyzed in lung nodule assessment and early cancer detection while an algorithm combining clinical information enhanced the test performance.

clinical trials↗

bioRxiv2018

Comparative whole-genome analysis reveals genetic adaptation of the invasive pinewood nematode

Genetic adaptation to new environments is essential for invasive species. To explore the genetic underpinnings of invasiveness of a dangerous invasive species, the pinewood nematode (PWN) Bursaphelenchus xylophilus, we analysed the genome-wide variations of a large cohort of 55 strains isolated from both the native and introduced regions. Comparative analysis showed abundant genetic diversity existing in the nematode, especially in the native populations. Phylogenetic relationships and principal component analysis indicate a dominant invasive population/group (DIG) existing in China and expansion beyond, with few genomic variations. Putative origin and migration paths at a global scale were traced by targeted analysis of rDNA sequences. A progressive loss of genetic diversity was observed along spread routes. We focused on variations with a low frequency allele (<50%) in the native USA population but fixation in DIG, and a total of 25,992 single nuclear polymorphisms (SNPs) were screened out. We found that a clear majority of these fixation alleles originated from standing variation. Functional annotation of these SNP-harboured genes showed that adaptation-related genes are abundant, such as genes that encode for chemoreceptors, proteases, detoxification enzymes, and proteins involved in signal transduction and in response to stresses and stimuli. Some genes under positive selection were predicted. Our results suggest that adaptability to new environments plays essentially roles in PWN invasiveness. Genetic drift, mutation and strong selection drive the nematode to rapidly evolve in adaptation to new environments, which including local pine hosts, vector beetles, commensal microflora and other new environmental factors, during invasion process.

genomics↗

bioRxiv2018

Identifying associations in dense connectomes using structured kernel principal component regression

A powerful and computationally efficient multivariate approach is proposed here, called structured kernel principal component regression (sKPCR), for the identification of associations in the voxel-level dense connectome. The method can identify voxel-phenotype associations based on the voxels whole-brain connectivity pattern, which is applicable to detect linear and non-linear signals for both volume-based and surface-based functional magnetic resonance imaging (fMRI) data. For each voxel, our approach first extracts signals from the spatially smoothed connectivities by structured kernel principal component analysis, and then tests the voxel-phenotype associations via a general linear model. The method derives its power by appropriately modelling the spatial structure of the data. Simulations based on dense connectome data have shown that our method can accurately control the false-positive rate, and it is more powerful than many state-of-the-art approaches, such as the connectivity-wise general linear model (GLM) approach, multivariate distance matrix regression (MDMR), adaptive sum of powered score (aSPU) test, and least-square kernel machine (LSKM). To demonstrate the utility of our approach in real data analysis, we apply these methods to identify voxel-wise difference between schizophrenic patients and healthy controls in two independent resting-state fMRI datasets. The findings of our approach have a better between-sites reproducibility, and a larger proportion of overlap with existing schizophrenia findings. Code for our approach can be downloaded from https://github.com/weikanggong/vBWAS.

neuroscience↗

bioRxiv2017

Gene markers for exon capture and phylogenomics in ray-finned fishes

Gene capture coupled with the next generation sequencing has become one of the favorable methods in subsampling genomes for phylogenomic studies. Many target gene markers have been developed in plants, sharks, frogs, reptiles and others, but few have been reported in the ray-finned fishes. Here, we identified a suite of \"single-copy\" protein coding sequence (CDS) markers through comparing eight fish genomes, and tested them empirically in 83 species (33 families and 11 orders) of ray-finned fishes. Sorting through the markers according to their completeness and phylogenetic decisiveness in taxa tested resulted in a selection of 4,434 markers, which were proven to be useful in reconstructing phylogenies of the ray-finned fishes at different taxonomic level. We also proposed a strategy of refining baits (probes) design a posteriori based on empirical data. The markers that we have developed may fill a gap in the tool kit of phylogenomic study in vertebrates.

evolutionary biology↗

bioRxiv2016

Statistical testing and power analysis for brain-wide association study

The identification of connexel-wise associations, which involves examining functional connectivities between pairwise voxels across the whole brain, is both statistically and computationally challenging. Although such a connexel-wise methodology has recently been adopted by brain-wide association studies (BWAS) to identify connectivity changes in several mental disorders, such as schizophrenia, autism and depression [Cheng et al., 2015a,b, 2016], the multiple correction and power analysis methods designed specifically for connexel-wise analysis are still lacking. Therefore, we herein report the development of a rigorous statistical framework for connexel-wise significance testing based on the Gaussian random field theory. It includes controlling the family-wise error rate (FWER) of multiple hypothesis testings using topological inference methods, and calculating power and sample size for a connexel-wise study. Our theoretical framework can control the false-positive rate accurately, as validated empirically using two resting-state fMRI datasets. Compared with Bonferroni correction and false discovery rate (FDR), it can reduce false-positive rate and increase statistical power by appropriately utilizing the spatial information of fMRI data. Importantly, our method considerably reduces the computational complexity of a permutation-or simulation-based approach, thus, it can efficiently tackle large datasets with ultra-high resolution images. The utility of our method is shown in a case-control study. Our approach can identify altered functional connectivities in a major depression disorder dataset, whereas existing methods failed. A software package is available at https://github.com/weikanggong/BWAS.

neuroscience↗