Biology subjects

Khan, M. A.

Publications and source records attributed to Khan, M. A..

33 records · Page 2Linked to original sources

bioRxiv2023

The variable domain from the mitochondrial fission mechanoenzyme Drp1 promotes liquid-liquid phase separation

Dynamins are an essential superfamily of mechanoenzymes that remodel membranes and often contain a "variable domain" (VD) important for regulation. For the mitochondrial fission dynamin, Drp1, a regulatory role for the VD is demonstrated by mutations that can elongate, or fragment, mitochondria. How the VD encodes inhibitory and stimulatory activity is unclear. Here, isolated VD is shown to be intrinsically disordered (ID) yet undergoes a cooperative transition in the stabilizing osmolyte TMAO. However, the TMAO stabilized state is not folded and surprisingly appears as a condensed state. Other co-solutes including known molecular crowder Ficoll PM 70, also induce a condensed state. Fluorescence recovery after photobleaching experiments reveal this state to be liquid-like indicating the VD undergoes a liquid-liquid phase separation under crowding conditions. These crowding conditions also enhance binding to cardiolipin, a mitochondrial lipid, raising the possibility that phase separation may enable rapid tuning of Drp1 assembly necessary for fission.

biophysics↗

bioRxiv2023

PERK arm of UPR selectively regulates ferroptosis in colon cancer cells by modulating the expression of SLC7A11 (System Xc-)

Ferroptosis, a genetically and biochemically distinct form of programmed cell death, is characterised by an iron-dependent accumulation of lipid peroxides. Therapy-resistant tumor cells display vulnerability toward ferroptosis. Endoplasmic Reticulum (ER) stress and Unfolded Protein Response (UPR) play a critical role in cancer cells to become therapy resistant. Tweaking the balance of UPR to make cancer cells susceptible to ferroptotic cell death could be an attractive therapeutic strategy. To decipher the emerging contribution of ER-stress in the ferroptotic process, we observe that ferroptosis inducer RSL3 promotes UPR (PERK, ATF6, and IRE1), along with overexpression of cystine-glutamate transporter SLC7A11 (System Xc-). Exploring the role of a particular UPR arm in modulating SLC7A11 expression and subsequent ferroptosis, we notice that PERK is selectively critical in inducing ferroptosis in colorectal carcinoma. PERK inhibition reduces ATF4 expression and recruitment to the promoter of SLC7A11 and results in its downregulation. Loss of PERK function not only primes cancer cells for increased lipid peroxidation but also limits in vivo colorectal tumor growth, demonstrating active signs of ferroptotic cell death in situ. Further, by performing TCGA data mining and using colorectal cancer patient samples, we demonstrate that the expression of PERK and SLC7A11 is positively correlated. Overall, our experimental data indicate that PERK is a negative regulator of ferroptosis and loss of PERK function sensitizes colorectal cancer cells to ferroptosis. Therefore, small molecule PERK inhibitors hold huge promise as novel therapeutics and their potential can be harnessed against the apoptosis-resistant condition.

cancer biology↗

bioRxiv2023

Photobiomodulation Therapy for a Novel Olfactory Dysfunction Ischemic Stroke Model

A.BackgroundIschemic stroke typically accompanies numerous disorders ranging from somatosensory dysfunction to cognitive impairments, inflicting its patients with various neurologic symptoms. Among pathologic outcomes, post-stroke olfactory dysfunction is frequently observed. Despite the well-known prevalence, therapy options for such compromised olfaction are limited, likely due to the complexity of the olfactory bulb architecture, which encompasses both the peripheral and central nervous systems. As photobiomodulation (PBM) emerged for treating stroke-associated symptoms, the effectiveness of PBM on the stroke-induced impairment of the olfactory function was explored. PurposeTo address the efficacy of PBM therapy on the olfactory bulb damage caused by ischemic stroke using both behavioral and histologic and inflammatory markers in the newly developed stroke mouse models. MethodsNovel mouse models with olfactory dysfunction were prepared using photothrombosis (PT) in the olfactory bulb on day 0. Moreover, post-PT PBM was performed daily from day 2 to day 7 by irradiating the olfactory bulb using an 808 nm laser with the fluence of 40 J/cm2 (325 mW/cm2 for 2 minutes per day). The buried food test (BFT) was used for scoring behavioral acuity in the food-deprived mice to assess the olfactory function before PT, after PT, and after PBM. Histopathological examinations and cytokine assays were performed on the mouse brains harvested on day 8. ResultsThe results from BFT were specific to the individual, with positive correlations between the baseline latency time measured before PT and alterations at the ensuing stages for both the PT and PT+PBM groups. Also in both groups, the correlation analysis showed a significant positive relationship between the early and late latency time changes independent of PBM, implicating a common recovery mechanism. In particular, the PBM treatment largely accelerated the recovery of impaired olfaction after PT with the suppression of inflammatory cytokines while enhancing both the glial and vascular factors (e.g., GFAP, IBA-1, and CD31). ConclusionsThe PBM therapy during the acute phase of ischemia improves the compromised olfactory function by modulating the microenvuronment and tissue inflammation.

neuroscience↗

bioRxiv2022

Habitat suitability modeling of Himalayan Monal and Koklass Pheasant in Western Himalayas and Hindukush, Pakistan

The Himalayan pheasants are under the greatest threat due to habitat degradation, and loss. Quantifying geographical range and suitable habitat of a species can help in better management and conservation decisions. Himalayan Monal (Lophophorus impejanus) and Koklass (Pucrasia macrolopha) are endemic to the Himalayas and Hindukush mountains. This study aims to investigate habitat suitability of these pheasants in the western Himalayas and Hindukush. MaxEnt and Cringing models were used to document habitat suitability and to identify valleys with most suitable habitat. MaxEnt model displayed excellent predictive performance showing a strong prediction of the probability distribution and habitat. The area under cover (AUC) values quantified for the replicate runs were 0.994 ({+/-}0.001) and 0.991 ({+/-}0.005) for Himalayan Monal and Koklass pheasant respectively. The climatic parameters including temperature, precipitation of the warmest quarter (bio_18) contributed the maximum 21.3% and 23.5%, followed by annual precipitation (bio_12) 12.3% and 8.9% for habitat prediction of Monal and Koklass. The topographical variables, altitude, slope, and distance to settlements contributed 15.2%, 2.6%, and 16% in the Monal habitat prediction model while 8.4%, 10.5%, and 15.8% for the Koklass habitat prediction model respectively. We quantified highly suitable (844.4 sq. km), moderately suitable (2819.42 sq. km), and less suitable (3933.09 sq. km) habitat for Monal pheasant. Whereas, highly suitable habitat for Koklass pheasant was (611.5 sq. km), followed by moderately suitable (2551.3 sq. km), and less suitable (4494.11 sq. km). Bar Palas region of Koli Palas district, Jalkot and Kandia valley of district upper Kohistan and Kayal valley of district lower Kohistan were identified as core zones or hot spots for these pheasant species. Areas identified as core zone/hotspot and suitable habitat for the pheasant species should be legally protected for the conservation of pheasants.

ecology↗

bioRxiv2022

CRISPRi-based circuits for genetic computation in plants

Synthetic gene circuits can enable new cellular behaviours by integrating multiple input signals into customisable genetic programs. However, gene circuit development in plants has been limited by a lack of orthogonal and modular parts required for their construction. Here, we present a tool-kit of reversible CRISPRi-based gene circuits for use in plants. First, we created a range of engineered repressible promoters of different strengths and used them as integrators for the construction of NOT and NOR gates in Arabidopsis cells. Next, we determined the optimal processing system to express sgRNAs from RNA Pol II promoters to introduce NOR gate programmability and interface it with host regulatory sequences. Finally, we connected multiple NOR gates together in layered arrangements to create OR, NIMPLY, and AND logic functions. Our CRISPRi circuits are orthogonal, compact, reversible, programmable, and modular, providing a new platform for sophisticated and deliberate spatio-temporal control of gene expression in plants.

synthetic biology↗

bioRxiv2022

Differential gene expression profiling reveals potential biomarkers and pharmacological compounds against SARS-CoV-2: insights from machine learning and bioinformatics approaches

SARS-CoV-2 continues to spread and evolve worldwide, despite intense efforts to develop multiple vaccines and therapeutic options against COVID-19. Moreover, the precise role of SARS-CoV-2 in the pathophysiology of the nasopharyngeal tract (NT) is still unfathomable. Therefore, we used the machine learning methods to analyze 22 RNA-seq datasets from COVID-19 patients (n=8), recovered individuals (n=7), and healthy individuals (n=7) to find disease-related differentially expressed genes (DEGs). In comparison to healthy controls, we found 1960 and 153 DEG signatures in COVID-19 patients and recovered individuals, respectively. We compared dysregulated DEGs to detect critical pathways and gene ontology (GO) connected to COVID-19 comorbidities. In COVID-19 patients, the DEG- miRNA and DEG-transcription factors (TFs) interactions network analysis revealed that E2F1, MAX, EGR1, YY1, and SRF were the most highly expressed TFs, whereas hsa-miR-19b, hsa-miR-495, hsa-miR-340, hsa-miR-101, and hsa-miR-19a were the overexpressed miRNAs. Three chemical agents (Valproic Acid, Alfatoxin B1, and Cyclosporine) were abundant in COVID-19 patients and recovered individuals. Mental retardation, mental deficit, intellectual disability, muscle hypotonia, micrognathism, and cleft palate were the significant diseases associated with COVID-19 by sharing DEGs. Finally, we detected DEGs impacted by SARS-CoV-2 infection and mediated by TFs and miRNA expression, indicating that SARS-CoV-2 infection may contribute to various comorbidities. These pathogenetic findings can provide some crucial insights into the complex interplay between COVID-19 and the recovery stage and support its importance in the therapeutic development strategy to combat against COVID-19 pandemic. IMPORTANCEDespite it has now been over two years since the beginning of the COVID-19 pandemic, many crucial questions about SARS-CoV-2 infection and the different COVID-19 symptoms it causes remain unresolved. An intriguing question about COVID-19 is how SARS-CoV-2 interplays with the host during infection and how SARS-CoV-2 infection can cause so many disease symptoms. Our analysis of three different datasets (COVID-19, recovered, and healthy) revealed significantly higher DEGs in COVID-19 patients than recovered humans and healthy controls. Some of these DEGs were found to be co-expressed in both COVID-19 patients. They recovered humans supporting the notion that DEGs level is directly correlated with the viral load, disease progression, and different comorbidities. The protein-protein interaction consisting of 24 nodes and 72 edges recognized eight hub-nodes as potential hub-proteins (i.e., RPL4, RPS4X, RPL19, RPS12, RPL19, EIF3E, MT-CYB, and MT-ATP6). Protein-chemical interaction analysis identified three chemical agents (e.g., Valproic Acid, Alfatoxin B1, and Cyclosporine) enriched in COVID-19 patients and recovered individuals. Mental retardation, mental deficiency, intellectual disability, muscle hypotonia, micrognathism, and cleft palate were the significant diseases associated with COVID-19 by sharing DEGs.

bioinformatics↗

bioRxiv2022

Synthetic memory circuits for programmable cell reconfiguration in plants

Plant biotechnology predominantly relies on a restricted set of genetic parts with limited capability to customize spatiotemporal and conditional expression patterns. Synthetic gene circuits have the ability to integrate multiple customizable input signals through a processing unit constructed from biological parts, to produce a predictable and programmable output. Here, we present a suite of functional recombinase-based gene circuits for use in plants. We first established a range of key gene circuit components compatible with plant cell functionality. We then used these to develop a range of operational logic gates using the identify function (activation) and negation function (repression) in Arabidopsis protoplasts and in vivo, demonstrating their utility for programmable manipulation of transcriptional activity in a complex multicellular organism. Through utilization of genetic recombination these circuits create stable long-term changes in expression and recording of past stimuli. This highly-compact programmable gene circuit platform provides new capabilities for engineering sophisticated transcriptional programs and previously unrealised traits into plants.

synthetic biology↗

bioRxiv2021

Unfolding the Apoptotic Mechanism of Antioxidant Enriched-Leaves of Tabebuia pallida in EAC Cells

Targeting apoptosis is a promising approach to inhibit the abnormal cell proliferation of cancer progression. Existing anti-apoptotic drugs, many derived from chemical substances, have often failed to combat cancer development and progression. Therefore, identification of apoptosis-inducing anticancer agents from plant-derived sources has become a key aim in cancer research. The present study was designed to explore the regulation of apoptosis by Tabebuia pallida (T. pallida) using an Ehrlich Ascites Carcinoma (EAC) mouse model and compositional analysis by LC-ESI-MS/MS. Dried and powdered T. pallida leaves (TPL), stem bark (TPSB), root bark (TPRB) and flowers (TPF) were extracted with 80% methanol. Using cultured EAC cells and EAC-bearing mice with and without these extracts, anticancer activities were studied by assessing cytotoxicity and tumor cell growth inhibition, changes in life span of mice, and hematological and biochemical parameters. Apoptosis was analyzed by microscopy and expression of selected apoptosis-related genes (Bcl-2, Bcl-xL, NF{kappa}-B, PARP-1, p53, Bax, caspase-3 and -8) using RT-PCR. LC-ESI-MS analysis was performed to identify the major compounds from the most active extracts. In EAC mice compared with untreated controls, the TPL extract exhibited the highest cytotoxicity with significant tumor cell growth inhibition (p< 0.001), reduced ascites by body weight (p< 0.01), increased the life span (p<0.001), normalized blood parameters (RBC/WBC counts), and increased the levels of superoxide dismutase and catalase. TPL-treated EAC cells showed apoptotic characteristics of membrane blebbing, chromatin condensation and nuclear fragmentation, and caspase-3 activation, compared with untreated EAC cells. Moreover, annexin V-FITC and propidium iodide signals were greatly enhanced in response to TPL treatment, indicating apoptosis induction. Pro- and anti-apoptotic signaling after TPL treatment demonstrated up-regulated p53, Bax and PARP-1, and down-regulated NF{kappa}-B, Bcl-2 and Bcl-xL expression, suggesting that TPL shifts the balance of pro- and anti-apoptotic genes towards cell death. LC-ESI-MS data of TPL showed a mixture of glycosides, lapachol, and quercetin antioxidant and its derivatives that were significantly linked to cancer cell targets. In conclusion, the TPL extract of T. pallida possesses significant anticancer activity. The tumor suppressive mechanism is due to apoptosis induced by activation of antioxidant enzymes and caspases and mediated by a change in the balance of pro- and anti-apoptotic genes that promotes cell death. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/426226v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@1112faaorg.highwire.dtl.DTLVardef@1505d1dorg.highwire.dtl.DTLVardef@1115a2aorg.highwire.dtl.DTLVardef@36a915_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2020

Cadmium interference with iron sensing reveals transcriptional programs sensitive and insensitive to reactive oxygen species

Iron (Fe) is an essential micronutrient whose uptake is tightly regulated to prevent either deficiency or oxidative stress. Cadmium (Cd) is a non-essential heavy metal that induces both Fe-deficiency and oxidative stress; however, the mechanisms underlying these Cd-induced responses are still elusive. Here we explored Cd-induced Fe-associated responses in wildtype Arabidopsis and opt3-2, a mutant that over-accumulates Fe. Gene expression profiling revealed a large overlap between transcripts induced by Fe-deficiency and Cd exposure in wildtype plants and the opt3 mutant. Interestingly, vascular-localized Fe-responsive genes were found to be highly induced by Cd even in the presence of high Fe and H2O2 levels, suggesting that Cd impairs Fe sensing. It was recently shown that Fe-S cluster-containing proteins AtNEET, play a role in Fe sensing. Our data shows that Cd negatively impacts both the stability and Fe-S transfer activity of AtNEET. Altogether, our data indicate that Fe-deficiency responses are governed by multiple inputs and that a hierarchical regulation of Fe-deficiency responses prevents the induction of specific gene networks when Fe and H2O2 levels are high. Other Cd/Fe-responsive genes however, are insensitive to this negative feedback regulation suggesting that their induction is the result of an impaired Fe sensing as opposed to the traditional view of Cd/Fe uptake competition at the root level.Highlight Cadmium induces an iron-deficiency response often explained by root uptake competition; here we show that Cd also impairs Fe sensing in leaves, even when Fe is in sufficient quantities.Competing Interest StatementThe authors have declared no competing interest.View Full Text

plant biology↗

bioRxiv2020

Genetic analysis confirms the presence of Dicrocoelium dendriticum in the Himalaya ranges of Pakistan.

Lancet liver flukes of the genus Dicrocoelium (Trematoda: Digenea) are recognised parasites of domestic and wild herbivores. The aim of the present study was to address a lack of knowledge of lancet flukes in the Himalaya ranges of Pakistan by characterising Dicrocoelium species collected from the Chitral valley. The morphology of 48 flukes belonging to eight host populations was examined in detail and according to published keys, they were identified as either D. dendriticum or Dicrocoelium chinensis. PCR and sequencing of fragments of ribosomal cistron DNA, and cytochrome oxidase-1 (COX-1) and NADH dehydrogenase-1 (ND-1) mitochondrial DNA from 34, 14 and 3 flukes revealed 10, 4 and 1 unique haplotypes, respectively. Single nucleotide polymorphisms in these haplotypes were used to differentiate between D. chinensis and D. dendriticum, and confirm the molecular species identity of each of the lancet flukes as D. dendriticum. Phylogenetic comparison of the D. dendriticum rDNA, COX-1 and ND-1 sequences with those from D. chinensis, Fasciola hepatica and Fasciola gigantica species was performed to assess within and between species variation and validate the use of species-specific markers for D. dendriticum. Genetic variations between D. dendriticum populations derived from different locations in the Himalaya ranges of Pakistan illustrate the potential impact of animal movements on gene flow. This work provides a proof of concept for the validation of species-specific D. dendriticum markers and is the first molecular confirmation of this parasite species from the Himalaya ranges of Pakistan. The characterisation of this parasite will allow research questions to be addressed on its ecology, biological diversity, and epidemiology.

genetics↗

bioRxiv2020

Identification of Deleterious Single Nucleotide Polymorphism (SNP)s in the Human TBX5 Gene & Prediction of Their Structural & Functional Consequences: An In Silico approach

T-box transcription factor 5 (TBX5) gene encodes the transcription factor TBX5, which plays a crucial role in developing the heart and upper limbs. Damaging single nucleotide variants in this gene alters the protein structure, disturbs the functions of TBX5, and ultimately causes Holt-Oram Syndrome (HOS). By analyzing available single nucleotide polymorphism information in the dbSNP database, this study was designed to identify the most deleterious TBX5 SNPs through silico approaches and predict their structural and functional consequences. Fifty-eight missense substitutions were found damaging by sequences homology-based tools like SIFT and PROVEAN and structure homology-based tools like PolyPhen-2. These SNPs were further scrutinized by various disease association meta-predictor tools. Additionally, the conservation profile of amino acid residues, their surface accessibility, stability, and structural integrity of the native protein upon mutations was assessed. From these analyses, finally 5 SNPs were detected as the most damaging ones [rs1565941579 (P85S), rs1269970792 (W121R), rs772248871 (V153D), rs769113870 (E208D), and rs1318021626 (I222N)]. Analyses of stop-loss, nonsense, UTR, and splice site SNPs were also conducted. Through integrative bioinformatics analyses, this study has identified SNPs that are deleterious to the TBX5 protein structure and have the potential to cause HOS. Further wet-lab experiments can validate these findings.

genetics↗

bioRxiv2019

Exponential Growth of Glioblastoma In Vivo Driven by Rapidly Dividing and Outwardly Migrating Cancer Stem Cells

How overall tumor growth emerges from the properties of functionally heterogeneous tumor cell subpopulations is a fundamental question of cancer biology. Here we combined lineage tracing, continuous monitoring of tumor mass, proliferation assays and transcriptomics with mathematical modeling and statistical inference to dissect the growth of glioblastoma in mice. We found that tumors grow exponentially at the rate of symmetric divisions of brain tumor stem cells (BTSCs). Spatial modeling predicts, and data show, that BTSCs accumulate at the tumor rim rather than in the core. The physiological differentiation hierarchy downstream of BTSCs is preserved in mice and humans: transit amplifying progenitors give rise to terminally differentiated cells. Consistent with our quantification of the mechanisms underlying tumor growth, molecular data show elevated expression of cell cycle-and migration-related genes in BTSCs. Our systematic approach reveals fundamental properties of glioblastoma and may be transferable to the study of other animal models of cancer.

cancer biology↗

bioRxiv2019

Developing critical thinking in STEM education through inquiry-based writing in the laboratory classroom

Laboratory pedagogy is moving away from step-by-step instructions and toward inquiry-based learning (IBL), but only now developing methods for integrating inquiry-based writing (IBW) practices into the laboratory course. Based on an earlier proposal (Science 332:919 (2011)), we designed and implemented an IBW sequence in a university bioinformatics course.\n\nWe automatically generated unique, double-blinded, biologically plausible DNA sequences for each student. After guided instruction, students investigated sequences independently and responded through IBW writing assignments. IBW assignments were structured as condensed versions of a scientific research paper, and because the sequences were double blinded, they were also assessed as authentic science and evaluated on clarity and persuasiveness.\n\nWe piloted the approach in a seven-day workshop (35 students) at Perdana University Graduate School of Medicine in Kuala Lumpur. We observed dramatically improved student engagement and indirect evidence of improved learning outcomes over a similar workshop without IBW. Based on student feedback, initial discomfort with the writing component abated in favor of an overall positive response and increasing comfort with the high demands of student writing. Similarly encouraging results were found in a semester length undergraduate module at the National University of Singapore (155 students).

scientific communication and education↗

bioRxiv2018

Polymerization Kinetics Stability, Volumetric Changes, Apatite Precipitation, Strontium Release and Fatigue of Novel Bone Composites for Vertebroplasty

PurposeThe aim was to determine effects of diluent monomer and monocalcium phosphate monohydrate (MCPM) on polymerization kinetics and volumetric stability, apatite precipitation, strontium release and fatigue of novel dual-paste composites for vertebroplasty.\n\nMaterials and methodsPolypropylene (PPGDMA) or triethylene (TEGDMA) glycol dimethacrylates (25 wt%) diluents were combined with urethane dimethacrylate (70 wt%) and hydroxyethyl methacrylate (5 wt%). 70 wt% filler containing glass particles, glass fibers (20 wt%) and polylysine (5 wt%) was added. Benzoyl peroxide and MCPM (10 or 20 wt%) or N-tolyglycine glycidyl methacrylate and tristrontium phosphate (15 wt%) were included to give initiator or activator pastes. Commercial PMMA (Simplex) and bone composite (Cortoss) were used for comparison.\n\nATR-FTIR was used to determine thermal activated polymerization kinetics of initiator pastes at 50-80 {degrees}C. Paste stability, following storage at 4-37 {degrees}C, was assessed visually or through mixed paste polymerization kinetics at 25 {degrees}C. Polymerization shrinkage and heat generation were calculated from final monomer conversions. Subsequent expansion and surface apatite precipitation in simulated body fluid (SBF) were assessed gravimetrically and via SEM. Strontium release into water was assessed using ICP-MS. Biaxial flexural strength (BFS) and fatigue properties were determined at 37 {degrees}C after 4 weeks in SBF.\n\nResultsPolymerization profiles all exhibited an inhibition time before polymerization as predicted by free radical polymerization mechanisms. Initiator paste inhibition times and maximum reaction rates were described well by Arrhenius plots. Plot extrapolation, however, underestimated lower temperature paste stability. Replacement of TEGDMA by PPGDMA, enhanced paste stability, final monomer conversion, water-sorption induced expansion and strontium release but reduced polymerisation shrinkage and heat generation. Increasing MCPM level enhanced volume expansion, surface apatite precipitation and strontium release. Although the experimental composite flexural strengths were lower compared to those of commercially available Simplex, the extrapolated low load fatigue lives of all materials were comparable.\n\nConclusionsIncreased inhibition times at high temperature give longer predicted shelf-life whilst stability of mixed paste inhibition times is important for consistent clinical application. Increased volumetric stability, strontium release and apatite formation should encourage bone integration. Replacing TEGDMA by PPGDMA and increasing MCPM could therefore increase suitability of the above novel bone composites for vertebroplasty. Long fatigue lives of the composites may also ensure long-term durability of the materials.

bioengineering↗

bioRxiv2018

Microbiome-TP53 Gene Interaction in Human Lung Cancer

BackgroundLung cancer is the leading cancer diagnosis worldwide and the number one cause of cancer deaths. Exposure to cigarette smoke, the primary risk factor in lung cancer, reduces epithelial barrier integrity and increases susceptibility to infections. Herein, we hypothesized that somatic mutations together with cigarette smoke generate a dysbiotic microbiota that is associated with lung carcinogenesis. Using lung tissue from controls (n=33) and cancer cases (n=143), we conducted 16S rRNA bacterial gene sequencing, with RNA-seq data from lung cancer cases in The Cancer Genome Atlas (n=1112) serving as the validation cohort.\n\nResultsOverall, we demonstrate a lower alpha diversity in normal lung as compared to non-tumor adjacent or tumor tissue. In squamous cell carcinoma (SCC) specifically, a separate group of taxa were identified, in which Acidovorax was enriched in smokers (P =0.0013). Acidovorax temporans was identified by fluorescent in situ hybridization within tumor sections, and confirmed by two separate 16S rRNA strategies. Further, these taxa, including Acidovorax, exhibited higher abundance among the subset of SCC cases with TP53 mutations, an association not seen in adenocarcinomas (AD).\n\nConclusionsThe results of this comprehensive study show both a microbiome-gene and microbiome-exposure interactions in SCC lung cancer tissue. Specifically, tumors harboring TP53 mutations, which can damage epithelial function, have a unique bacterial consortia which is higher in relative abundance in smoking-associated SCC. Given the significant need for clinical diagnostic tools in lung cancer, this study may provide novel biomarkers for early detection.

cancer biology↗