Biology subjects

Kaur, H.

Publications and source records attributed to Kaur, H..

At least 55 records · Page 3Linked to original sources

bioRxiv2023

Cup is essential for oskar mRNA translational repression during early Drosophila oogenesis

The proper timing of mRNA translation is crucial across many biological systems for processes such as intercellular communication, body pattern formation, and morphogenesis. The main D. melanogaster posterior determinant, oskar, is maternally transcribed, but only translated when properly localized at the oocytes posterior cortex. Bruno 1 and Cup are two effector proteins known to participate in multiple aspects of oskar mRNA regulation. Current model describes a mechanism in which Bruno 1 is necessary for Cups recruitment to oskar mRNA, and Bruno 1 is indispensable for its translational repression. Here, we reveal that the Bruno 1-Cup interaction, as well as their interdependent influence on each others mRNA and protein expression, lead to precise oskar mRNA regulation during early oogenesis. We show that these factors stably associate with the oskar mRNA in vivo, but surprisingly, Bruno 1s stable association with oskar mRNA depends on Cup, while Bruno 1 is not necessary for Cup association to oskar mRNA. During early oogenesis, Cup, not Bruno 1, is the essential factor for oskar mRNA repression. Cup is a crucial P-body member that maintains proper P-body morphology during oogenesis, as well as it is necessary for oskar mRNAs association with P-bodies, thus driving the translational repression and stability of oskar mRNA. Our experimental results collectively suggest a regulatory mechanism where a feedback loop between Bruno 1 and Cup coordinates oskar mRNA regulation in the egg chamber allowing for proper development to occur.

developmental biology↗

bioRxiv2023

High quality genome and transcriptome data for two new species of Mantamonas, a deep-branching eukaryote clade

Mantamonads were long considered to represent an "orphan" lineage in the tree of eukaryotes, likely branching near the most frequently assumed position for the root of eukaryotes. Recent phylogenomic analyses have placed them as part of the "CRuMs" supergroup, along with collodictyonids and rigifilids. This supergroup appears to branch at the base of Amorphea, making it of special importance for understanding the deep evolutionary history of eukaryotes. However, the lack of representative species and complete genomic data associated with them has hampered the investigation of their biology and evolution. Here, we isolated and described two new species of mantamonads, Mantamonas vickermani sp. nov. and Mantamonas sphyraenae sp. nov., for each of which we generated transcriptomic sequence data, as well as a high-quality genome for the latter. The estimated size of the M. sphyraenae genome is 25 Mb; our de novo assembly appears to be highly contiguous and complete with 9,416 predicted protein-coding genes. This near-chromosome-scale genome assembly is the first described for the CRuMs supergroup.

genomics↗

bioRxiv2023

Composition of nasopharyngeal microbiota in individuals with SARS-COV-2 infection across three COVID-19 waves in India

Multiple variants of the SARS-CoV-2 virus have been plaguing the world through successive waves of infection over the past three years. Studies by independent research groups across geographies have shown that the microbiome composition in COVID-19 patients (CP) differ from that of healthy individuals (CN). However, such observations were based on limited-sized sample-sets collected primarily from the early days of the pandemic. Here, we study the nasopharyngeal microbiota in COVID-19 patients, wherein the samples have been collected across the three COVID-19 waves witnessed in India, which were driven by different variants of concern. We also present the variations in microbiota of symptomatic vs asymptomatic COVID-19 patients. The nasopharyngeal swabs were collected from 589 subjects providing samples for diagnostics purposes at Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India. CP showed a marked shift in the microbial diversity and composition compared to CN, in a wave-dependent manner. Rickettsiaceae was the only family that was noted to be consistently depleted in CP samples across the waves. The genera Staphylococcus, Anhydrobacter, Thermus, and Aerococcus were observed to be highly abundant in the symptomatic CP patients when compared to the asymptomatic group. In general, we observed a decrease in the burden of opportunistic pathogens in the host microbiota during the later waves of infection. To our knowledge, this is the first longitudinal study which was designed to understand the relation between the evolving nature of the virus and the changes in the human nasopharyngeal microbiota. Such studies not only pave way for better understanding of the disease pathophysiology but also help gather preliminary evidence on whether interventions to the host microbiota can help in better protection or faster recovery.

microbiology↗

bioRxiv2022

Risk assessment of cancer patients based on HLA-I alleles, neobinders and expression of cytokines

Advancements in cancer immunotherapy have shown significant outcomes in treating various types of cancers. In order to design effective immunotherapy, it is important to understand immune response of a patient based on its genomic profile. We compute prognostic biomarkers from 8346 cancer patients for twenty types of cancer. These prognostic biomarkers has been computed based on i) presence of 352 human leucocyte antigen class-I (HLA-I), ii) 660959 tumor-specific HLA1 neobinders and iii) expression profile of 153 cytokines. It was observed that survival risk of cancer patients depends on presence of certain type of HLA-I alleles; for example LIHC cancer patients with HLA-A*03:01 are on lower risk. Our analysis indicate that neobinders of HLA-I alleles have high correlation with overall survival of certain type of cancer patients. For example HLA-B*07:02 binders have 0.49 correlation with survival of LUSC and -0.77 with KICH cancer patients. It is clear from above analysis that HLA and their binders have major role in survival of cancer patients suffering from different types of cancer. In addition, we compute prognostic biomarkers for 20 types of cancer based on each type of cytokine expression. Higher expression of few cytokines is survival favourable like IL-2 for BLCA cancer patients whereas IL-5R survival unfavourable for KICH cancer patients. In order to facilitate scientific community we developed a web-based platform CancerHLA1 that maintain raw and analyzed data (https://webs.iiitd.edu.in/raghava/cancerhla1/).

cancer biology↗

bioRxiv2022

Detection and Role of Feline Apolipoprotein B mRNA-editing Enzyme Catalytic Polypeptide Subunit 3G-Like Protein in Feline Cells and Tissues

The innate host defence system is designed to resist pathogenic microorganism infections. Despite the compelling scientific evidence, our understanding of the full potential of the mechanism is still unclear due to the complex interactions between hosts and invaders. We previously reported latency in cat mucosal infected with low-dose cell-associated feline immunodeficiency virus (102 and 103 infected cells). Here we investigated the expression of Apolipoprotein B mRNA-editing enzyme catalytic subunit 3G (APOBEC3G or A3G) in feline cells and tissues and whether its presence antagonizes the viral pre-integration complex resulting in partial or complete FIV latency. Total RNA and protein lysates were collected from cell lines, blood, and tissue samples. Real-time RT-PCR and western blot assays were used to quantify fA3G-like protein in cats exposed to high versus low-dose cell-associated FIV. We consistently detected fA3G-like protein in mock T-cell lines (E-CD4+, MYA-1, Crandell feline kidney cells) and primary bone marrow-derived macrophages with variable expressions in feline peripheral blood mononuclear cells (PBMC). In addition, the fA3G-like protein was found to interact with FIV group-specific antigen (Gag) protein through immunoprecipitation assays. The protein expression was utterly abrogated following FIV infection. However, in lytic FIV infection (in vivo), fA3G-like protein decreased in early post-infection, whereas latently infected cats showed stable expression. These data are the first report of the fA3G-like protein expression in felines and its abrogation in lytic but not in latent FIV-infected individuals. These results might provide new insight into the role of fA3G-like protein in the host defence mechanism against retrovirus infections.

cell biology↗

bioRxiv2022

Glioma-BioDP: Database for Visualization of Molecular Profiles to Improve Prognosis of Brain Cancer

Cancer researchers often seek user-friendly interactive tools for validation, exploration, analysis, and visualization of molecular profiles in cancer patient samples. To aid researchers working on both low-and high-grade gliomas, we developed Glioma-BioDP, a web tool for exploration and visualization of RNA and protein expression profiles of interest in these tumor types. Glioma-BioDP is an extended version of our earlier published tool GBM-BioDP. In this version we have included expression data from both the low-and high-grade glioma patient samples from The Cancer Genome Atlas and enabled querying by mRNA, microRNA, and protein level expression data from Illumina HiSeq and RPPA platforms respectively. Glioma-BioDP enables users to explore the association of genes, proteins, and miRNA expression with molecular and/or histological subtypes of gliomas, surgical resection status and survival. The prognostic significance and visualization of the selected expression profiles can be explored using interactive utilities provided. This tool also enables potential validation and generation of new hypotheses of novel therapies impacting gliomas that aid in personalization of treatment for optimum outcomes. AvailabilityGlioma-BioDP web tool with user manual is available from: https://glioma-biodp.nci.nih.gov Contact: uma@mail.nih.gov

cancer biology↗

bioRxiv2022

Identifying novel regulators of placental development using time series transcriptomic data and network analyses

The placenta serves as a connection between the mother and the fetus during pregnancy, and provides the fetus with oxygen, nutrients, and growth hormones. However, the regulatory mechanisms and dynamic gene interaction networks underlying early placental development are understudied. Here, we generated RNA sequencing (RNA-seq) data from mouse fetal placenta tissues at embryonic day (e) 7.5, e8.5 and e9.5 to identify genes with timepoint-specific expression, then inferred gene interaction networks to analyze highly connected network modules. We determined that timepoint-specific gene network modules associated with distinct developmental processes, and with similar expression profiles to specific human placental cell populations. From each module, we obtained hub genes and their direct neighboring genes, which were predicted to govern placental functions. We confirmed that four novel candidate regulators identified through our analyses regulate cell migration in the HTR-8/SVneo cell line. Upon conclusion of this study, we were able to predict several novel regulators of placental development using network analysis of bulk RNA-seq data. Our findings and analysis approaches will be valuable for future studies investigating the transcriptional landscape of early placental development.

developmental biology↗

bioRxiv2022

Identification of Transient Intermediates During Spliceosome Activation by Single Molecule Fluorescence Microscopy

Spliceosome activation is the process of creating the catalytic site for RNA splicing and occurs de novo on each intron following spliceosome assembly. Dozens of factors bind to or are released from the activating spliceosome including the Lsm2-8 heteroheptameric ring that binds the U6 small nuclear RNA (snRNA) 3-end. Lsm2-8 must be released to permit active site stabilization by the Prp19-containing complex (NineTeen Complex, NTC); however, little is known about the temporal order of events and dynamic interactions that lead up to and follow Lsm2-8 release. We have used colocalization single molecule spectroscopy (CoSMoS) to visualize Lsm2-8 dynamics during activation of yeast spliceosomes. Lsm2-8 is recruited as a component of the tri-snRNP and is released after integration of the Prp19-containing complex (NineTeen Complex, NTC). Despite Lsm2-8 and the NTC being mutually exclusive in existing cryo-EM structures of yeast B complex spliceosomes, we identify a transient intermediate containing both [Formula] and provide a kinetic framework for its formation and transformation during activation. Prior to [Formula] assembly, the NTC rapidly and reversibly samples the spliceosome suggesting a mechanism for preventing NTC sequestration by defective spliceosomes that fail to properly activate. In complementary ensemble assays, we show that a base-pairing dependent ternary complex can form between Lsm2-8 and U2 and U6 helix II RNAs. Together our data suggest a Hfq-like function for Lsm2-8 in maintaining U2/U6 helix II integrity before it can be transferred to the NTC by transient formation of the [Formula] spliceosome. Significance StatementThe spliceosome active site is created de novo during activation and involves numerous conformational and compositional changes. Here, we define a kinetic pathway for yeast spliceosome activation using single molecule fluorescence that includes transient intermediates not previously identified. Real-time measurements allow us to uncover rapid, reversible sampling interactions of the NineTeen Complex (NTC) that may prevent its accumulation on defective spliceosomes. By analogy with bacterial Hfq, we propose that the homologous Lsm2-8 proteins stabilize U2/U6 helix II during activation before the helix is transferred to the NTC in a short-lived spliceosome containing both Lsm2-8 and the NTC. Our data demonstrate how single molecule studies of activation can reveal kinetically-competent intermediates and complement cryo-EM studies of stalled or inhibited complexes.

biochemistry↗

bioRxiv2022

In Silico transcriptional analysis of asymptomatic and severe COVID-19 patients reveals the susceptibility of severe patients to other comorbidities and non-viral pathological conditions

COVID-19 is a severe respiratory disease caused by SARS-CoV-2, a novel human coronavirus. The host response to SARS-CoV-2 infection is not clearly understood. Patients infected with SARS-CoV-2 exhibit heterogeneous intensity of symptoms, i.e., asymptomatic, mild, and severe. Moreover, effects on organs also vary from person to person. These heterogeneous responses pose pragmatic hurdles for implementing appropriate therapy and management of COVID-19 patients. Post-COVID complications pose another major challenge in managing the health of these patients. Thus, understanding the impact of disease severity at the molecular level is vital to delineate the precise host response and management. In the current study, we performed a comprehensive transcriptomics analysis of publicly available seven asymptomatic and eight severe COVID-19 patients. Exploratory data analysis using Principal Component Analysis (PCA) showed the distinct clusters of asymptomatic and severe patients. Subsequently, the differential gene expression analysis using DESeq2 identified 1,224 significantly upregulated genes (logFC>= 1.5, p-adjusted value <0.05) and 268 significantly downregulated genes (logFC<= -1.5, p-adjusted value <0.05) in severe samples in comparison to asymptomatic samples. Eventually, Gene Set Enrichment Analysis (GSEA) of upregulated genes revealed significant enrichment of terms, i.e., anti-viral and anti-inflammatory pathways, secondary infections, Iron homeostasis, anemia, cardiac-related, etc. Gene set enrichment analysis of downregulated genes indicates lipid metabolism, adaptive immune response, translation, recurrent respiratory infections, heme-biosynthetic pathways, etc. In summary, severe COVID-19 patients are more susceptible to other health issues/concerns, non-viral pathogenic infections, atherosclerosis, autoinflammatory diseases, anemia, male infertility, etc. And eventually, these findings provide insight into the precise therapeutic management of severe COVID-19 patients and efficient disease management.

bioinformatics↗

bioRxiv2021

Whole genome resequencing and comparative genome analysis of three Puccinia striiformis f. sp. tritici pathotypes prevalent in India

Stripe rust disease of wheat, caused by Puccinia striiformis f. sp. tritici, (Pst) is one of the most serious diseases of wheat worldwide. In India, virulent stripe rust races have been constantly evolving in the North-Western Plains Zone leading to the failure of some of the most widely grown resistant varieties in the region. With the goal of studying the recent evolution of virulent races in this region, we conducted whole-genome sequencing of three prevalent Indian Pst pathotypes Pst46S119, Pst78S84 and Pst110S119. We assembled 58.62, 58.33 and 55.78 Mb of Pst110S119, Pst46S119 and Pst78S84 genome, respectively. Pathotypes were found to be highly heterozygous. Comparative phylogenetic analysis indicated the recent evolution of pathotypes Pst110S119 and Pst78S84 from Pst46S119. Pathogenicity-related genes classes (CAZyme, proteases, effectors, and secretome proteins) were identified and found to be under positive selection. Higher rate of gene family expansion was also observed in the three pathotypes. A strong association between the effector genes and transposable elements may be the source of the rapid evolution of these strains. Phylogenetic analysis differentiated the Indian races in this study from other known US, European, African and Asian races. Diagnostic markers developed for the identification of different Pst pathotypes will help tracking of yellow rust at farmers field and strategizing resistance gene deployment.

bioinformatics↗

bioRxiv2021

Transcriptomic analysis of DNA damage response in zebrafish embryos under simulated microgravity

Space is an extremely hostile environment. Traveling to space has numerous effects on the body of the astronauts at a molecular level. As space agencies prepare for long-term missions, it becomes important to investigate these problems and address them. Thus, in the current study, we assessed the impact of simulated microgravity on the basic pathways especially DNA damage response. We identified a total of 7542 significantly differentially expressed genes. Out of these genes, 4504 were found to be up-regulated while 3038 were down-regulated in the simulated microgravity group in comparison to controls. Pathway enrichment analysis revealed that simulated microgravity has an effect on vital basic biological processes like DNA damage repair, peptide transport, and metabolism. To explore if the same pathways were also altered in humans, we explored the NASA twin study data and found that DDR was also significantly affected in the astronaut but due to ionizing radiation. Upon further investigation, we found that 62 genes belonging to the DDR pathway were mutually differentially expressed in Scott Kelly and the zebrafish embryos. However, there were 29 significantly differentially expressed genes belonging to the DDR pathway in zebrafish embryos that were not found to be differentially expressed in Scott Kelly. Out of these 29 genes, 14 were specific to zebrafish. Upon further investigation, we found that the DDR pathway is affected differently in simulated microgravity as compared to ionizing radiation. These observations provide a preliminary look into the difference in DDR induced by the different factors of spaceflight.

bioinformatics↗

bioRxiv2021

In silico Analysis of Transcriptomic Profiling and Affected Biological pathways in Multiple Sclerosis

Multiple sclerosis (MS) is a chronic autoimmune, inflammatory neurological disease that is widely associated with Grey and white matter degradation due to the demyelination of axons. Thus exposing the underlying causes of this condition can lead to a novel treatment approach for Multiple Sclerosis. The total RNA microarray processed data from GEO for Multiple sclerotic patients was comprehensively analyzed to find out underlying differences between Grey Matter lesions (GML), Normal appearing Grey Matter (NAGM), and Control Grey matter at the transcriptomics level. Thus, in the current study, we performed various bioinformatics analyses on transcriptional profiles of 184 samples including 105 NAGM, 37 GML, and 42 Controls obtained from the NCBI-Bio project (PRJNA543111). First, exploratory data analysis based on gene expression data using principal component analysis (PCA) depicted distinct patterns between GML and CG samples. Subsequently, the Welchs T-test differential gene expression analysis identified 15,525 significantly differentially expressed genes (p.adj value <0.05, Fold change(>=+/-1.5) between these conditions. This study reveals the genes like CREB3L2, KIF5B, WIPI1, EP300, NDUFA1, ATG101, AND TAF4 as the key features that may substantially contribute to loss of cognitive functions in Multiple sclerosis and several other neurodegenerative disorders. Further, this study also proposes genes associated with Huntingtons disease in Multiple sclerotic patients. Eventually, the results presented here reveal new insights into MS and how it affects the development of male primary sexual characteristics.

neuroscience↗

bioRxiv2021

Analysis of Gene Expression Profiles to study Malaria Vaccine Dose Efficacy & Immune Response Modulation.

Malaria is a life-threatening disease, and the Africa is still one of the most affected endemic regions despite years of policy to limit infection and transmission rates. Further, studies into the variable efficacy of the vaccine are needed to provide a better understanding of protective immunity. Thus, the current study is designed to delineate the effect of the different vaccination doses on the transcriptional profiles of subjects to determine its efficacy and understand the molecular mechanisms underlying the protection this vaccine provides. Here, we used gene expression profiles of pre and post-vaccination patients after various doses of RTS,S based on 275 and 583 samples collected from the GEO datasets. At first, exploratory data analysis based Principal component analysis (PCA) shown the distinct pattern of different doses. Subsequently, differential gene expression analysis using edgeR revealed the significantly (FDR <0.005) 158 down-regulated and 61 upregulated genes between control vs. Controlled Human Malaria Infection (CHMI) samples. Further, enrichment analysis of significant genes using Annotation and GAGE tools delineate the involvement of CCL8, CXCL10, CXCL11, XCR1, CSF3, IFNB1, IFNE, IL12B, IL22, IL6, IL27, etc.,genes which found to be upregulated after earlier doses but downregulated after the 3rd dose in cytokine-chemokine pathways. Notably, we identified 13 cytokine genes whose expression significantly varied during three doses. Eventually, these findings give insight to the dual role of cytokine responses in malaria pathogenesis and variations in their expression patterns after various doses of vaccination involved in protection.

bioinformatics↗

bioRxiv2021

Gestationally-Dependent Immune Organization at the Maternal-Fetal Interface

The immune system and placenta have a dynamic relationship across gestation to accommodate fetal growth and development. High-resolution characterization of this maternal- fetal interface is necessary to better understand the immunology of pregnancy and its complications. We developed a single-cell framework to simultaneously immuno-phenotype circulating, endovascular, and tissue-resident cells at the maternal-fetal interface throughout gestation, discriminating maternal and fetal contributions. Our data reveal distinct immune profiles across the endovascular and tissue compartments with tractable dynamics throughout gestation that respond to a systemic immune challenge in a gestationally-dependent manner. We uncover that mononuclear phagocytes and neutrophils drive the temporal immune composition of the placenta with remarkably diverse populations, including PD-L1-expressing subsets having compartmental and early gestational bias. Our approach and accompanying datasets provide a resource for additional investigations into gestational immunology and evoke a more significant role for the innate immune system in establishing the microenvironment of early pregnancy. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/449807v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@6235corg.highwire.dtl.DTLVardef@fba572org.highwire.dtl.DTLVardef@12b0af4org.highwire.dtl.DTLVardef@dc44da_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2021

ProCanBio: a database of manually curated biomarkers for Prostate Cancer

BackgroundProstate Cancer is the second lethal malignancy in men worldwide. In the past, numerous research groups investigated the omics profiles of patients and scrutinized biomarkers for the diagnosis and prognosis of prostate cancer. However, information related to the biomarkers is widely scattered across numerous resources in complex textual format, which poses hindrance to understand the tumorigenesis of this malignancy and scrutinization of robust signature. To the best of authors knowledge, there is no resource that can consolidate the information contained in all the published literature. ResultsHere, we present ProCanBio, a manually curated database that maintains detailed data on 2053 entries of potential prostate cancer biomarkers obtained from 412 publications in user friendly tabular format. Among them, 766 protein-based, 488 RNA-based, 157 genomic mutations, 261 miRNA-based, and 122 are metabolites-based biomarkers. To explore the information in the resource, a web-based interactive platform was developed with searching, and browsing facilities. ProCanBio is freely available and is compatible with most web browsers and devices. Eventually, we anticipated this resource will be highly useful for the research community involved in the area of prostate malignancy. AvailabilityProCanBio is available at: https://webs.iiitd.edu.in/raghava/procanbio/

cancer biology↗

bioRxiv2021

Isolation and characterization of SARS-CoV-2 VOC, 20H/501Y.V2, from UAE travelers

Multiple SARS-CoV-2 variants have been emerged and created serious public health in the affected countries. The variant of Concern associated with high transmissibility, disease severity and escape mutations is threat to vaccination program across the globe. Travel has been important factor in spread of SARS-CoV-2 variants worldwide. India has also witnessed the dreadful effect of these SARS-CoV-2 variants. Here, we report the Isolation and characterization of SARS-CoV-2 VOC, 20H/501Y.V2 (B.1.351), from UAE travelers to India. The virus isolate would be useful to determine the efficacy of the currently available vaccines in India.

microbiology↗

bioRxiv2021

In Silico Analysis and Characterization of Differentially Expressed Genes to Distinguish Glioma Stem Cells from Normal Neural Stem Cells

Glioblastoma multiforme (GBM) is a heterogeneous, invasive primary brain tumor that develops chemoresistance post therapy. Theories regarding the aetiology of GBM focus on transformation of normal neural stem cells (NSCs) to a cancerous phenotype or tumorigenesis driven via glioma stem cells (GSCs). Comparative RNA-Seq analysis of GSCs and NSCs can provide a better understanding of the origin of GBM. Thus, in the current study, we performed various bioinformatics analyses on transcriptional profiles of a total 40 RNA-seq samples including 20 NSC and 20 GSC, that were obtained from the NCBI-SRA (SRP200400). First, differential gene expression (DGE) analysis using DESeq2 revealed 348 significantly differentially expressed genes between GSCs and NSCs (padj. value <0.05, log2fold change [≥] 3.0 (for GSCs) and [≤] -3.0 (for NSCs)) with 192 upregulated and 156 downregulated genes in GSCs in comparison to NSCs. Subsequently, exploratory data analysis using principal component analysis (PCA) based on key significant genes depicted the clear separation between both the groups. Further, Hierarchical clustering confirmed the distinct clusters of GSC and NSC samples. Eventually, the biological enrichment analysis of the significant genes showed their enrichment in tumorigenesis pathways such as Wnt-signalling, VEGF-signalling and TGF-{beta}-signalling pathways. Conclusively, our study depicted significant differences in the gene expression patterns between NSCs and GSCs. Besides, we also identified novel genes and genes previously unassociated with gliomagenesis that may prove to be valuable in establishing diagnostic, prognostic biomarkers and therapeutic targets for GBM.

cancer biology↗

bioRxiv2021

A mechanistic model captures the emergence and implications of non-genetic heterogeneity and reversible drug resistance in ER+ breast cancer cells

Resistance to anti-estrogen therapy is an unsolved clinical challenge in successfully treating ER+ breast cancer patients. Acquisition of mutations can confer heritable resistance to cancer cells, enabling their clonal selection to establish a drug-resistant population. Recent studies have demonstrated that cells can tolerate drug treatment without any genetic alterations too; however, the mechanisms and dynamics of such non-genetic adaptation remain elusive. Here, we investigate coupled dynamics of epithelial-mesenchymal transition (EMT) in breast cancer cells and emergence of reversible drug resistance. Our mechanism-based model for the underlying regulatory network reveals that these two axes can drive one another, thus conferring bidirectional plasticity. This network can also enable non-genetic heterogeneity in a population of cells by allowing for six co-existing phenotypes: epithelial-sensitive, mesenchymal-resistant, hybrid E/M-sensitive, hybrid E/M-resistant, mesenchymal-sensitive and epithelial-resistant, with the first two ones being most dominant. Next, in a population dynamics framework, we exemplify the implications of phenotypic plasticity (both drug-induced and intrinsic stochastic switching) and/or non-genetic heterogeneity in promoting population survival in a mixture of sensitive and resistant cells, even in the absence of any cell-cell cooperation. Finally, we propose the potential therapeutic use of MET (mesenchymal-epithelial transition) inducers besides canonical anti-estrogen therapy to limit the emergence of reversible drug resistance. Our results offer mechanistic insights into empirical observations on EMT and drug resistance and illustrate how such dynamical insights can be exploited for better therapeutic designs.

cancer biology↗