Biology subjects

M, Y.

Publications and source records attributed to M, Y..

4 recordsLinked to original sources

bioRxiv2022

A synthetic lethal screen for Snail-induced enzalutamide resistance identifies JAK/STAT signaling as a therapeutic vulnerability in prostate cancer

Despite substantial improvements in the treatment landscape of prostate cancer, the evolution of hormone therapy-resistant and metastatic prostate cancer remains a major cause of cancer-related death globally. The mainstay of treatment for advanced prostate cancer is targeting of androgen receptor signaling, including androgen deprivation therapy plus second-generation androgen receptor blockade (e.g., enzalutamide, apalutamide, darolutamide), and/or androgen synthesis inhibition (abiraterone). While these agents have significantly prolonged the lives of patients with advanced prostate cancer, the evolution of resistance to these treatments in nearly universal. This therapy resistance is mediated by diverse mechanisms, including both androgen receptor-dependent mechanisms, such as androgen receptor mutations, amplifications, alternatively spliced isoforms, and structural rearrangements, as well as non-androgen receptor-mediated mechanisms, such as lineage plasticity toward neuroendocrine-like or epithelial-mesenchymal transition (EMT)-like lineages. Our prior work identified the EMT transcriptional regulator Snail as critical to hormonal therapy resistance and commonly detected in human metastatic prostate cancer. In the current study, we sought to interrogate the actionable landscape of EMT-mediated hormone therapy-resistant prostate cancer to identify synthetic lethality and collateral sensitivity approaches to treating this aggressive disease state. Using a combination of high-throughput drug screens and multi-parameter phenotyping by confluence imaging, ATP production, and phenotypic plasticity reporters of EMT, we identified candidate synthetic lethalities to Snail-mediated EMT in prostate cancer. These analyses identified multiple actionable targets, such as XPO1, PI3K/mTOR, aurora kinases, c-MET, polo-like kinases, and JAK/STAT as synthetic lethalities in Snail+ prostate cancer. We validated these targets in a subsequent validation screen in an LNCaP-derived model of resistance to sequential androgen deprivation and enzalutamide. This follow-up screen provided validation of inhibitors of JAK/STAT and PI3K/mTOR as therapeutic vulnerabilities for Snail+ and enzalutamide-resistant prostate cancer.

cancer biology↗

bioRxiv2022

Identification of potential antifibrinolytic compounds against kringle-1 and serine protease domain of plasminogen and kringle-2 domain of tissue-type plasminogen activator using combined virtual screening, molecular docking, and molecular dynamics simulation approaches.

The zymogen protease Plasminogen (Plg) and its active form plasmin (Plm) carry out important functions in the blood clot disintegration (breakdown of fibrin fibres) process. Inhibition of plasmin effectively reduces fibrinolysis to circumvent heavy bleeding. Currently, available Plm inhibitor tranexamic acid (TXA) that is used to treat severe hemorrhages is associated with an increased incidence of seizures which in turn were traced to gamma-aminobutyric acid antagonistic activity (GABAa) in addition to having multiple side effects. Fibrinolysis can be suppressed by targeting the three important protein domains: kringle-1 and serine protease domain of plasminogen and kringle-2 domain of tissue plasminogen activator. In the present study, combined approaches of structure-based virtual screening and molecular docking using Schrodinger Glide, AutoDock Vina, and ParDock/BAPPL+ were employed to identify potential hits from the ZINC database. Thereafter, the drug-likeness properties of the top three leads for each protein target were evaluated using Discovery Studio. Subsequently, a molecular dynamics simulation of 200ns for each protein-ligand complex was performed in GROMACS. The identified ligands are found to impart higher rigidity and stability to the protein-ligand complexes. Furthermore, the results were validated by performing the principal component analysis (PCA), and calculation of binding free energy using the Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) approach. The identified ligands occupy smaller phase space, form stable clusters and exhibit stronger non-bonded interactions. Thus, our findings can be useful for the development of promising anti-fibrinolytic agents. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/512028v2_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@b762fforg.highwire.dtl.DTLVardef@1c47591org.highwire.dtl.DTLVardef@1028dc1org.highwire.dtl.DTLVardef@a884ad_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2022

PD-L1 activity is associated with partial EMT and metabolic reprogramming in carcinomas

Immune evasion and metabolic reprogramming are hallmarks of cancer progression often associated with a poor prognosis and frequently present significant challenge for cancer therapies. Recent studies have emphasized on the dynamic interaction between immunosuppression and the dysregulation of energy metabolism in modulating the tumor microenvironment to promote cancer aggressiveness. However, a pan-cancer association among these two hallmarks, and a potent common driver for them - Epithelial-Mesenchymal Transition (EMT) - remains to be done. Here, our meta-analysis across 184 publicly available transcriptomic datasets as well as The Cancer Genome Atlas (TCGA) data reveals that an enhanced PD-L1 activity signature along with other immune checkpoint markers correlate positively with a partial EMT and elevated glycolysis signature but a reduced OXPHOS signature in many carcinomas. These trends were also recapitulated in single-cell RNA-seq time-course EMT induction data across cell lines. Furthermore, across multiple cancer types, concurrent enrichment of glycolysis and PD-L1 results in worse outcomes in terms of overall survival as compared to enrichment for only PD-L1 activity or expression. Our results highlight potential functional synergy among these interconnected axes of cellular plasticity in enabling metastasis and/or multi-drug resistance in cancer.

cancer biology↗

bioRxiv2022

The ELF3 transcription factor is associated with an epithelial phenotype and represses epithelial-mesenchymal transition

Epithelial-mesenchymal plasticity (EMP) involves bidirectional transitions between epithelial, mesenchymal and multiple intermediary hybrid epithelial/mesenchymal phenotypes. While the process of epithelial-mesenchymal transition (EMT) and its associated transcription factors are well-characterised, the transcription factors that promote mesenchymal-epithelial transition (MET) and stabilise hybrid E/M phenotypes are less well understood. Here, we analyse multiple publicly-available transcriptomic datasets at bulk and single-cell level and pinpoint ELF3 as a factor that is strongly associated with an epithelial phenotype and is inhibited during EMT. Using mechanism-based mathematical modelling, we also show that ELF3 inhibits the progression of EMT, suggesting ELF3 may be able to counteract EMT induction, including in the presence of EMT-inducing factors, such as WT1. Our model predicts that the MET induction capacity of ELF3 is stronger than that of KLF4, but weaker than that of GRHL2. Finally, we show that ELF3 levels correlates with worse patient survival in a subset of solid tumor types, suggesting cell-of-origin or lineage specificity in the prognostic capacity of ELF3.

cancer biology↗