Biology subjects

Nath, A.

Publications and source records attributed to Nath, A..

36 records · Page 2Linked to original sources

bioRxiv2024

Drugs Form Ternary Complexes with Human Liver Fatty Acid Binding Protein (FABP1) and FABP1 Binding Alters Drug Metabolism

Liver fatty acid binding protein (FABP1) binds diverse endogenous lipids and is highly expressed in the human liver. Binding to FABP1 alters the metabolism and homeostasis of endogenous lipids in the liver. Drugs have also been shown to bind to rat FABP1, but limited data is available for human FABP1 (hFABP1). FABP1 has a large binding pocket and multiple fatty acids can bind to FABP1 simultaneously. We hypothesized that drug binding to hFABP1 results in formation of ternary complexes and that FABP1 binding alters drug metabolism. To test these hypotheses native protein mass spectrometry (MS) and fluorescent 11-(dansylamino)undecanoic acid (DAUDA) displacement assays were used to characterize drug binding to hFABP1 and diclofenac oxidation by cytochrome P450 2C9 (CYP2C9) was studied in the presence and absence of hFABP1. DAUDA binding to hFABP1 involved high (Kd,1=0.2 {micro}M) and low affinity (Kd,2 >10 {micro}M) binding sites. Nine drugs bound to hFABP1 with Kd values ranging from 1 to 20 {micro}M. None of the tested drugs completely displaced DAUDA from hFABP1 and fluorescence spectra showed evidence of ternary complex formation. Formation of DAUDA-diclofenac-hFABP1 ternary complex was verified with native MS. Docking placed diclofenac in the portal region of FABP1 with DAUDA in the binding cavity. Presence of hFABP1 decreased the kcat and Km,u of diclofenac with CYP2C9 by [~]50% suggesting that hFABP1 binding in the liver will alter drug metabolism and clearance. Together, these results suggest that drugs form ternary complexes with hFABP1 and that hFABP1 interacts with CYP2C9. Significance statementMany commonly prescribed drugs bind FABP1 forming ternary complexes with FABP1 and the fluorescent fatty acid DAUDA. This suggests that in the human liver drugs will bind to apo-FABP1 and fatty acid bound FABP1. The high expression of FABP1 in the liver and binding of drugs to FABP1 will alter rates of drug metabolism in the liver.

pharmacology and toxicology↗

bioRxiv2022

ONC201/TIC10 enhances durability of mTOR inhibitor everolimus in metastatic ER+ breast cancer

The mTOR inhibitor, everolimus, is an important clinical management component of metastatic ER+ breast cancer. However, most patients develop resistance and progress on therapy, highlighting the need to discover strategies that increase mTOR inhibitor effectiveness. We developed ER+ breast cancer cell lines, sensitive or resistant to everolimus, and discovered that combination treatment of ONC201/TIC10 with everolimus inhibited cell growth in 2D/3D in vitro studies. We confirmed increased therapeutic response in primary patient cells progressing on everolimus, supporting clinical relevance. We show ONC201/TIC10, in metastatic ER+ breast cancer cells, mechanistically involves oxidative phosphorylation inhibition and stress response activation. Transcriptomic analysis in everolimus resistant breast patient tumors and mitochondrial functional assays in resistant cell lines demonstrated increased mitochondrial respiration dependency, contributing to ONC201/TIC10 sensitivity. We propose that ONC201/TIC10 and modulation of mitochondrial function may provide an effective add-on therapy strategy for patients with metastatic ER+ breast cancers resistant to mTOR inhibitors.

cancer biology↗

bioRxiv2022

Cancer cells communicate with macrophages to prevent T cell activation during development of cell cycle therapy resistance

Cancer cells evolve, acquire resistance to therapy and change their environment. One resistance mechanism involves altering communication with non-malignant cells in the tumor microenvironment (TME). By corrupting the signals for growth and survival, evolving cancer cells can engineer a pro-tumor TME. However, the specific interactions between malignant and non-malignant cells that predispose drug resistance and their changes during treatment remain widely unknown. Here we examine the composition, communication, and phenotypic diversity of tumor-associated cell populations in serial biopsies from early-stage ER+ breast cancers. These patients received either endocrine therapy (letrozole) alone or in combination with a CDK4/6 cell cycle inhibitor ribociclib, and were analyzed using single-cell RNA sequencing (scRNAseq). Our analyses reveal cancer cells from ribociclib resistant tumors stimulate macrophage differentiation towards an immune-suppressive phenotype through upregulation of a broad diversity of cytokines and growth factors. This shift in phenotype leads to reduced macrophage cell IL-15/-18 crosstalk with CD8+ T-cell via IL-2/15RA/18R receptors, resulting in diminished T-cell activation and recruitment. Thus, cancer communication promoting an immune-cold TME predispose tumors to develop CDK4/6 inhibitor resistance, and that the beneficial effects of cell cycle inhibitors through blocking cancer cell proliferation must be balanced against their known inhibitory effect on immune cell division and activation. An optimal treatment strategy will require coupling the prevention of cancer division with activation of an effective cytotoxic T-cell response.

cancer biology↗

bioRxiv2022

Imbalanced immune response and dysregulation of neural functions underline fatal opportunistic encephalitis caused by astrovirus

The incidence of infections of the central nervous system (CNS) in humans is increasing due to emergence and reemergence of pathogens and an increase in the number of immunocompromised patients. Many viruses are opportunists and can invade the CNS if the immune response of the host is impaired. Here we investigate neuropathogenesis of a rare CNS infection in immunocompromised patients caused by astrovirus and show that it shares many features with another opportunistic infection of the CNS caused by human immunodeficiency virus. We show that astrovirus infects CNS neurons with a major impact on the brainstem. In the setting of impaired peripheral adaptive immunity, host responses in the astrovirus infected brain are skewed to the innate immune response with exuberant activation of microglia and macrophages. Astrovirus infection of neurons and responses by phagocytic cells lead to disrupted synaptic integrity, loss of afferent innervation related to infected neurons, and global impairment of both excitatory and inhibitory neurotransmission. The response employed in the CNS against opportunistic viruses, such as astrovirus and HIV, may be a common compensatory defense mechanism which inadvertently leads to loss of neural functions due to the hosts exuberant innate immune response to pathogens when adaptive immunity is impaired.

microbiology↗

bioRxiv2022

RNAinsecta: A tool for prediction of pre-microRNA in insects using machine learning algorithms.

Pre-MicroRNAs are the hairpin loops which produces microRNAs that negatively regulate gene expression in several organisms. In insects, microRNAs participate in several biological processes including metamorphosis, reproduction, immune response, etc. Numerous tools have been designed in recent years to predict pre-microRNA using binary machine learning classifiers where predictive models are trained with true and pseudo pre-microRNA hairpin loops. Currently however, there are no existing tool that is exclusively designed for insect pre-microRNA detection. In this experiment we trained machine learning classifiers such as Random Forest, Support Vector Machine, Logistic Regression and k-Nearest Neighbours to predict pre-microRNA hairpin loops in insects while using Synthetic Minority Over-sampling Technique and Near-Miss to handle the class imbalance. The trained model on Support Vector Machine achieved accuracy of 92.19% while the Random Forest attained an accuracy of 80.28% on our validation dataset. These models are hosted online as web application called RNAinsecta. Further, searching target for the predicted pre-microRNA in insect model organism Drosophila melanogaster has been provided in RNAinsecta using miRanda at the backend where experimentally validated genes regulated by microRNA are collected from miRTarBase as target sites. RNAinsecta is freely available at https://rnainsecta.in

bioinformatics↗

bioRxiv2022

Antibiotic-induced recombination in Gram-negative bacteria requires the formation of double-strand breaks

Recombination is an essential process in bacterial drug resistance evolution. Fluoroquinolones, an important class of antibiotics, are known to stimulate recombination in Escherichia coli. When bacteria are exposed to antibiotics other than fluoroquinolones, including strong up-regulators of recombination pathways, there is no detectable change in the recombination level. Here we explore why fluoroquinolones, but not other antimicrobials, increase recombination rates. Fluoroquinolones, in contrast to other antibiotics, generate DNA double-strand breaks (DSBs). We tested whether other drugs that also cause double-strand breaks, such as mitomycin C and bleomycin, also affect bacterial recombination rates with consistent increases in recombination. A positive correlation between the number of DSBs and the recombination frequency was found. The manipulation of the level of DSBs directly impacted the recombination frequency. Our results highlight that only antibiotics that induce DNA double-strand breaks are more probable to increase genetic diversity via recombination. The stimulation of recombination by DSB-causing antimicrobials is an additional factor leading to the risk of antibiotic resistance evolution.

microbiology↗

bioRxiv2022

Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain

Survivors of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection frequently experience lingering neurological symptoms, including impairment in attention, concentration, speed of information processing and memory. This long-COVID cognitive syndrome shares many features with the syndrome of cancer therapy-related cognitive impairment (CRCI). Neuroinflammation, particularly microglial reactivity and consequent dysregulation of hippocampal neurogenesis and oligodendrocyte lineage cells, is central to CRCI. We hypothesized that similar cellular mechanisms may contribute to the persistent neurological symptoms associated with even mild SARS-CoV-2 respiratory infection. Here, we explored neuroinflammation caused by mild respiratory SARS-CoV-2 infection - without neuroinvasion - and effects on hippocampal neurogenesis and the oligodendroglial lineage. Using a mouse model of mild respiratory SARS-CoV-2 infection induced by intranasal SARS-CoV-2 delivery, we found white matter-selective microglial reactivity, a pattern observed in CRCI. Human brain tissue from 9 individuals with COVID-19 or SARS-CoV-2 infection exhibits the same pattern of prominent white matter-selective microglial reactivity. In mice, pro-inflammatory CSF cytokines/chemokines were elevated for at least 7-weeks post-infection; among the chemokines demonstrating persistent elevation is CCL11, which is associated with impairments in neurogenesis and cognitive function. Humans experiencing long-COVID with cognitive symptoms (48 subjects) similarly demonstrate elevated CCL11 levels compared to those with long-COVID who lack cognitive symptoms (15 subjects). Impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss in subcortical white matter were evident at 1 week, and persisted until at least 7 weeks, following mild respiratory SARS-CoV-2 infection in mice. Taken together, the findings presented here illustrate striking similarities between neuropathophysiology after cancer therapy and after SARS-CoV-2 infection, and elucidate cellular deficits that may contribute to lasting neurological symptoms following even mild SARS-CoV-2 infection.

neuroscience↗

bioRxiv2021

Dendro-somatic synaptic inputs to ganglion cells violate receptive field and connectivity rules in the mammalian retina

In retinal neurons, morphology strongly influences visual response features. Ganglion cell (GC) dendrites ramify in distinct strata of the inner plexiform layer (IPL) so that GCs responding to light increments (ON) or decrements (OFF) receive appropriate excitatory inputs. This vertical stratification prescribes response polarity and ensures consistent connectivity between cell types, whereas the lateral extent of GC dendritic arbors typically dictates receptive field (RF) size. Here, we identify circuitry in mouse retina that contradicts these conventions. A2 amacrine cells are interneurons understood to mediate "cross-over" inhibition by relaying excitatory input from the ON layer to inhibitory outputs in the OFF layer. Ultrastructural and physiological analyses show, however, that some A2s deliver powerful inhibition to OFF GC somas and proximal dendrites in the ON layer, rendering their inhibitory RFs smaller than their dendritic arbors. This OFF pathway, avoiding entirely the OFF region of the IPL, challenges several tenets of retinal circuitry.

neuroscience↗

bioRxiv2021

Probing Interactions of Therapeutic Antibodies with Serum via Second Virial Coefficient Measurements

Antibody-based therapeutics are the fastest growing drug class on the market, used to treat aggressive forms of cancer, chronic autoimmune conditions, and numerous other disease states. While the specificity, affinity, and versatility of therapeutic antibodies can provide an advantage over traditional small molecule drugs, their development and optimization can be much more challenging and time-consuming. This is, in part, because the ideal formulation buffer systems used for in vitro characterization inadequately reflect the crowded biological environments (serum, endosomal lumen, etc.) that these drugs experience once administered to a patient. Such environments can perturb the binding of antibodies to their antigens and receptors, as well as homo- and hetero-aggregation, in ways that are incompletely understood, thereby altering therapeutic effect and disposition. While excluded volume effects are classically thought to favor binding, weak interactions with co-solutes in crowded conditions can inhibit binding. The second virial coefficient (B2) parameter quantifies such weak interactions and can be determined by a variety of techniques in dilute solution, but analogous methods in complex biological fluids are not well established. Here, we demonstrate that fluorescence correlation spectroscopy (FCS) is able to measure diffusive B2 values directly in undiluted serum. Apparent second virial coefficient (B2,app) measurements of antibodies in serum reveal that changes in the balance between attractive and repulsive interactions can dramatically impact global nonideality. Furthermore, our findings suggest that the common approach of isolating specific components and completing independent cross-term virial coefficient measurements is an incomplete representation of nonideality in serum. The approach presented here could enrich our understanding of the effects of biological environments on proteins in general, and advance the development of therapeutic antibodies and other protein-based therapeutics. STATEMENT OF SIGNIFICANCEWe present FCS as an orthogonal method to traditional methods for characterizing weak, nonspecific homo- and hetero-interactions through determination of self- and cross-term second virial coefficients, respectively. We also characterize weak interactions between therapeutic antibodies and serum components through determination of an apparent second virial coefficient (B2,app) directly in undiluted serum. Our results suggest that global nonideality effects are antibody-dependent, and that attractive and repulsive interactions with co-solutes are occurring simultaneously. This approach could advance our understanding of the impact of nonideality to the biophysical and pharmacological properties of therapeutic antibodies and other engineered proteins in relevant biological environments, and could accelerate the development and optimization of protein-based therapeutics.

biophysics↗

bioRxiv2020

Cell states beyond transcriptomics: integrating structural organization and gene expression in hiPSC-derived cardiomyocytes

We present a quantitative co-analysis of RNA abundance and sarcomere organization in single cells and an integrated framework to predict subcellular organization states from gene expression. We used human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes expressing mEGFP-tagged alpha-actinin-2 to develop quantitative image analysis tools for systematic and automated classification of subcellular organization. This captured a wide range of sarcomeric organization states within cell populations that were previously difficult to quantify. We performed RNA FISH targeting genes identified by single cell RNA sequencing to simultaneously assess the relationship between transcript abundance and structural states in single cells. Co-analysis of gene expression and sarcomeric patterns in the same cells revealed biologically meaningful correlations that could be used to predict organizational states. This study establishes a framework for multi-dimensional analysis of single cells to study the relationships between gene expression and subcellular organization and to develop a more nuanced description of cell states. Graphical AbstractTranscriptional profiling and structural classification was performed on human induced pluripotent stem cell-derived cardiomyocytes to characterize the relationship between transcript abundance and subcellular organization. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/081083v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@8f89c4org.highwire.dtl.DTLVardef@19dc813org.highwire.dtl.DTLVardef@1ba7c20org.highwire.dtl.DTLVardef@2b3daa_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2020

Exploiting collateral sensitivity controls growth of mixed culture of sensitive and resistant cells and decreases selection for resistant cells

BackgroundCDK4/6 inhibitors such as ribociclib are becoming widely used targeted therapies in hormone-receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) breast cancer. However, cancers can advance due to drug resistance, a problem in which tumor heterogeneity and evolution are key features. MethodsRibociclib-resistant HR+/HER2-CAMA-1 breast cancer cells were generated through long-term ribociclib treatment. Characterization of sensitive and resistant cells were performed using RNA sequencing and whole exome sequencing. Lentiviral labeling with different fluorescent proteins enabled us to track the proliferation of sensitive and resistant cells under different treatments in a heterogeneous, 3D spheroid coculture system using imaging microscopy and flow cytometry. ResultsTranscriptional profiling of sensitive and resistant cells revealed the downregulation of the G2/M checkpoint in the resistant cells. Exploiting this acquired vulnerability; resistant cells exhibited collateral sensitivity for the Wee-1 inhibitor, adavosertib (AZD1775). The combination of ribociclib and adavosertib achieved additional antiproliferative effect exclusively in the cocultures compared to monocultures, while decreasing the selection for resistant cells. ConclusionsOur results suggest that optimal antiproliferative effects in heterogeneous cancers can be achieved via an integrative therapeutic approach targeting sensitive and resistant cancer cell populations within a tumor, respectively.

systems biology↗

bioRxiv2020

Antimicrobial peptide induced-stress renders Staphylococcus aureus susceptible to toxic nucleoside analogues

Cationic antimicrobial peptides (AMPs) are active immune effectors of multicellular organisms and also considered as new antimicrobial drug candidates. One of the problems encountered when developing AMPs as drugs is the difficulty to reach sufficient killing concentrations under physiological conditions. Here, using pexiganan, a cationic peptide derived from a host defence peptide of the African clawed frog and the first AMP developed into an antibacterial drug, we studied if sub-lethal effects of AMPs can be harnessed to devise treatment combinations. We studied the pexiganan stress response of Staphylococcus aureus at sub-lethal concentrations using quantitative proteomics. Several proteins involved in nucleotide metabolism were elevated, suggesting a metabolic demand. We then show that S. aureus is highly susceptible to antimetabolite nucleoside analogues when exposed to pexiganan, even at sub-inhibitory concentrations. These findings could be used to enhance pexiganan potency while decreasing the risk of resistance emergence, and our findings can likely be extended to other antimicrobial peptides.

microbiology↗

bioRxiv2020

A 'one-two punch' therapy strategy to target chemoresistance in ER+ breast cancer

BackgroundCancer cell phenotypes evolve over the course of a tumors treatment. The phenotypes that emerge and disappear over time will be specific to each drug regimen and type of cancer. Chemotherapy remains one of the most common and effective treatments for metastatic breast cancer patients; however, resistance to chemotherapy inevitably emerges. Cancer chemotherapy treatment regimens are not designed to target emerging chemo-resistance, despite its clear importance in progressive cancer. This study focuses on finding sequential treatment strategies that target acquired chemo-resistant states and optimize response to chemotherapy. MethodsIn this study, we used heterogeneous tumor samples from patients to identify subclones resistant to chemotherapy. Using flow cytometry for stem cell markers and DNA sequencing to define subclonal population changes, we measured the enrichment of cancer stem cell-like (CSL) phenotypes in subclones that survive chemotherapy. We then analyzed breast cancer patient tumor organoids and cell line acquisition of CSL traits following chemotherapy, as well as the ability of different drugs to reverse acquired resistance, using flow cytometry, mammosphere assays, and single cell RNA-sequencing analysis. ResultsWe show that in progressive estrogen receptor positive (ER+) metastatic breast cancer patients, resistant tumor subclones that emerge following chemotherapy have increased CSL abundance. Further, in vitro organoid growth of ER+ patient cancer cells also shows that chemotherapy treatment leads to increased abundance of ALDH+/CD44+ CSL cells. Chemotherapy induced CSL abundance is blocked by treatment with a pan-HDAC inhibitor, belinostat. Further, belinostat treatment diminished both mammosphere formation and size following chemotherapy, also indicating a decrease in progenitor CSL traits. HDAC inhibitors specific to class IIa (HDAC4, HDAC5) and IIb (HDAC6) were shown to primarily reverse the chemo-resistant CSL state. Single-cell RNA sequencing analysis with patient samples showed that HDAC targets and MYC signaling were promoted by chemotherapy and inhibited upon HDAC inhibitor treatment. ConclusionThese findings indicate that HDAC inhibition can block chemotherapy-induced drug resistant phenotypes with one-two punch strategy in refractory breast cancer cells.

cancer biology↗

bioRxiv2020

Rapid formation of peptide/lipid co-aggregates by the amyloidogenic seminal peptide PAP248-286

Protein/lipid co-assembly is an understudied phenomenon that is important to the function of antimicrobial peptides as well as the pathological effects of amyloid. Here we study the co-assembly process of PAP248-286, a seminal peptide that displays both amyloid-forming and antimicrobial activity. PAP248-286 is a fragment of prostatic acid phosphatase and has been reported to form amyloid fibrils, known as semen-derived enhancer of viral infection (SEVI), that enhance the viral infectivity of HIV. We find that in addition to forming amyloid, PAP248-286 much more readily assembles with lipid vesicles into peptide/lipid co-aggregates that resemble amyloid fibrils in some important ways but are a distinct species. The formation of these co-aggregates, which we term "messicles", is controlled by the peptide:lipid (P:L) ratio and by the lipid composition. The optimal P:L ratio is around 1:10 and at least 70% anionic lipid is required for co-aggregate formation. Once formed, messicles are not disrupted by subsequent changes in P:L ratio. We propose that messicles form through a polyvalent assembly mechanism, where a critical surface density of PAP248-286 on liposomes enables peptide-mediated particle bridging into larger species. Even at ~100-fold lower PAP248-286 concentrations, messicles form at least 10-fold faster than amyloid fibrils. It is therefore possible that, some or all of the biological activities assigned to SEVI, the amyloid form of PAP248-286, could instead be attributed to a PAP248-286/lipid co-aggregate. More broadly speaking, this work provides a potential framework for the discovery and characterization of peptide/lipid co-aggregates by other amyloid-forming proteins and antimicrobial peptides. Statement of SignificancePAP248-286, a fragment of prostatic acid phosphatase, forms amyloid thought to enhances the infectivity of many viruses, including HIV. This amyloid, termed semen-derived enhancer of viral infection (SEVI), has been assigned responsibility for all of PAP248-286s biological activities, while the monomer is thought to be inactive. However, SEVI formation is quite slow and requires very high concentrations of PAP248-286. Here, we show that PAP248-286 can instead assemble much more rapidly with lipid membranes to form another species, mechanistically and morphologically distinct from both monomer and SEVI amyloid. We have characterized this new species, which could play a role in the biological activities currently ascribed to SEVI. Additionally, our proposed mechanism for peptide/lipid co-assembly could apply to other biologically important systems.

biophysics↗

bioRxiv2019

Identification of a novel tedizolid resistance mutation in rpoB of methicillin-resistant Staphylococcus aureus

A tedizolid-resistant isolate of MRSA was selected by serial passage. Whole genome sequencing revealed only a single nucleotide variant in rpoB. Cross-resistance to linezolid, chloramphenicol, and quinupristin-dalfopristin was observed but susceptibility to other drugs including rifampin was unchanged. Models of the RNA-polymerase-ribosomal complex revealed that the mutated residue was unlikely to interact directly with the oxazolidinone binding site. This is the first time that rpoB mutation has been associated with resistance to the PhLOPSa antimicrobials.

microbiology↗

bioRxiv2019

Interplay of disordered and ordered regions of a human small heat shock protein yields an ensemble of \"quasi-ordered\" states.

Small heat shock proteins (sHPSs) are natures \"first responders\" to cellular stress, interacting with affected proteins to prevent their aggregation. Little is known about sHSP structure beyond its structured -crystallin domain (ACD), which is flanked by disordered regions. In the human sHSP HSPB1, the disordered N-terminal region (NTR) represents nearly 50% of the sequence. Here, we present a hybrid approach involving NMR, hydrogen-deuterium exchange mass spectrometry, and modeling to provide the first residue-level characterization of the NTR. The results support a model in which multiple grooves on the ACD interact with specific NTR regions, creating an ensemble of \"quasi-ordered\" NTR states that can give rise to the known heterogeneity and plasticity of HSPB1. Phosphorylation-dependent interactions inform a mechanism by which HSPB1 is activated under stress conditions. Additionally, we examine the effects of disease-associated NTR mutations on HSPB1 structure and dynamics, leveraging our emerging structural insights.

biochemistry↗

bioRxiv2019

Discovering novel long non-coding RNA predictors of anticancer drug sensitivity beyond protein-coding genes

Large-scale cancer cell line screens have identified thousands of protein-coding genes (PCGs) as biomarkers of anticancer drug response. However, systematic evaluation of long non-coding RNAs (lncRNAs) as pharmacogenomic biomarkers has so far proven challenging. Here, we study the contribution of lncRNAs as drug response predictors beyond spurious associations driven by correlations with proximal PCGs, tissue-lineage or established biomarkers. We show that, as a whole, the lncRNA transcriptome is equally potent as the PCG transcriptome at predicting response to hundreds of anticancer drugs. Analysis of individual lncRNAs transcripts associated with drug response reveals nearly half of the significant associations are in fact attributable to proximal cis-PCGs. However, adjusting for effects of cis-PCGs revealed significant lncRNAs that augment drug response predictions for most drugs, including those with well-established clinical biomarkers. In addition, we identify lncRNA-specific somatic alterations associated with drug response by adopting a statistical approach to determine lncRNAs carrying somatic mutations that undergo positive selection in cancer cells. Lastly, we experimentally demonstrate that two novel lncRNA, EGFR-AS1 and MIR205HG, are functionally relevant predictors of anti-EGFR drug response.

bioinformatics↗

bioRxiv2018

Cancer eQTLs can be determined from heterogeneous tumor gene expression data by modeling variation in tumor purity

Expression quantitative trait loci (eQTLs) identified using tumor gene expression data could affect gene expression in cancer cells, tumor-associated normal cells, or both. Here, we demonstrate a method to identify eQTLs affecting expression in cancer cells by modeling the statistical interaction between genotype and tumor purity. Only one-third of breast cancer risk variants, identified as eQTLs from a conventional analysis, could be confidently attributed to cancer cells. The remaining variants could affect cells of the tumor microenvironment, such as immune cells and fibroblasts. Deconvolution of tumor eQTLs will help determine how inherited polymorphisms influence cancer risk, development, and treatment response.

genomics↗