Mutually exclusive teams-like patterns of gene regulation characterize phenotypic heterogeneity along the noradrenergic-mesenchymal axis in neuroblastoma.

Neuroblastoma is the most frequent extracranial pediatric tumor and leads to 15% of all cancer-related deaths in children. Tumor relapse and therapy resistance in neuroblastoma are driven by phenotypic plasticity and heterogeneity between noradrenergic (NOR) and mesenchymal (MES) cell states. Despite the importance of this phenotypic plasticity, the dynamics and molecular patterns associated with these bidirectional cell-state transitions remain relatively poorly understood. Here, we analyze multiple RNA-seq datasets at both bulk and single-cell resolution, to understand the association between NOR- and MES-specific factors. We observed that NOR-specific and MES-specific expression patterns are largely mutually exclusive, exhibiting a "teams-like" behavior among the genes involved, reminiscent of our earlier observations in lung cancer and melanoma. This antagonism between NOR and MES phenotypes was also associated with metabolic reprogramming and with immunotherapy targets PD-L1 and GD2 as well as with experimental perturbations driving the NOR-MES and/or MES-NOR transition. Further, these "teams-like" patterns were seen only among the NOR- and MES-specific genes, but not in housekeeping genes, possibly highlighting a hallmark of network topology enabling cancer cell plasticity.

Characterizing heterogeneity along EMT and metabolic axes in colorectal cancer reveals underlying consensus molecular subtype-specific trends.

Colorectal cancer (CRC) is highly heterogeneous with variable survival outcomes and therapeutic vulnerabilities. A commonly used classification system in CRC is the Consensus Molecular Subtypes (CMS) based on gene expression patterns. However, how these CMS categories connect to axes of phenotypic plasticity and heterogeneity remains unclear. Here, in our analysis of CMS-specific TCGA data and 101 bulk transcriptomic datasets, we found the epithelial phenotype score to be consistently positively correlated with scores of glycolysis, OXPHOS and FAO pathways, while PD-L1 activity scores positively correlated with mesenchymal phenotype scoring, revealing possible interconnections among plasticity axes. Single-cell RNA-sequencing analysis of patient samples revealed that that CMS2 and CMS3 subtype samples were relatively more epithelial as compared to CMS1 and CMS4. CMS1 revealed two subpopulations: one close to CMS4 (more mesenchymal) and the other closer to CMS2 or CMS3 (more epithelial), indicating a partial EMT-like behavior. Consistent observations were made in single-cell analysis of metabolic axes and PD-L1 activity scores. Together, our results quantify the patterns of two functional interconnected axes of phenotypic heterogeneity - EMT and metabolic reprogramming - in a CMS-specific manner in CRC.

A systems-level analysis of the mutually antagonistic roles of RKIP and BACH1 in dynamics of cancer cell plasticity.

Epithelial-mesenchymal transition (EMT) is an important axis of phenotypic plasticity-a hallmark of cancer metastasis. Raf kinase-B inhibitor protein (RKIP) and BTB and CNC homology 1 (BACH1) are reported to influence EMT. In breast cancer, they act antagonistically, but the exact nature of their roles in mediating EMT and associated other axes of plasticity remains unclear. Here, analysing transcriptomic data, we reveal their antagonistic trends in a pan-cancer manner in terms of association with EMT, metabolic reprogramming and immune evasion via PD-L1. Next, we developed and simulated a mechanism-based gene regulatory network that captures how RKIP and BACH1 engage in feedback loops with drivers of EMT and stemness. We found that RKIP and BACH1 belong to two antagonistic 'teams' of players-while BACH1 belonged to the one driving pro-EMT, stem-like and therapy-resistant cell states, RKIP belonged to the one enabling pro-epithelial, less stem-like and therapy-sensitive phenotypes. Finally, we observed that low RKIP levels and upregulated BACH1 levels associated with worse clinical outcomes in many cancer types. Together, our systems-level analysis indicates that the emergent dynamics of underlying regulatory network enable the antagonistic patterns of RKIP and BACH1 with various axes of cancer cell plasticity, and with patient survival data.

Corrigendum to "Specific epigenetic regulators serve as potential therapeutic targets in idiopathic pulmonary fibrosis" [Heliyon Volume 8, Issue 8, August 2022, Article e09773].

[This corrects the article DOI: 10.1016/j.heliyon.2022.e09773.].

Emergent dynamics of underlying regulatory network links EMT and androgen receptor-dependent resistance in prostate cancer.

Advanced prostate cancer patients initially respond to hormone therapy, be it in the form of androgen deprivation therapy or second-generation hormone therapies, such as abiraterone acetate or enzalutamide. However, most men with prostate cancer eventually develop hormone therapy resistance. This resistance can arise through multiple mechanisms, such as through genetic mutations, epigenetic mechanisms, or through non-genetic pathways, such as lineage plasticity along epithelial-mesenchymal or neuroendocrine-like axes. These mechanisms of hormone therapy resistance often co-exist within a single patient's tumor and can overlap within a single cell. There exists a growing need to better understand how phenotypic heterogeneity and plasticity results from emergent dynamics of the regulatory networks governing androgen independence. Here, we investigated the dynamics of a regulatory network connecting the drivers of androgen receptor (AR) splice variant-mediated androgen independence and those of epithelial-mesenchymal transition. Model simulations for this network revealed four possible phenotypes: epithelial-sensitive (ES), epithelial-resistant (ER), mesenchymal-resistant (MR) and mesenchymal-sensitive (MS), with the latter phenotype occurring rarely. We observed that well-coordinated "teams" of regulators working antagonistically within the network enable these phenotypes. These model predictions are supported by multiple transcriptomic datasets both at single-cell and bulk levels, including in vitro EMT induction models and clinical samples. Further, our simulations reveal spontaneous stochastic switching between the ES and MR states. Addition of the immune checkpoint molecule, PD-L1, to the network was able to capture the interactions between AR, PD-L1, and the mesenchymal marker SNAIL, which was also confirmed through quantitative experiments. This systems-level understanding of the driver of androgen independence and EMT could aid in understanding non-genetic transitions and progression of such cancers and help in identifying novel therapeutic strategies or targets.

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 challenges for cancer therapies. Recent studies have highlighted 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. This 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 an 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. These results highlight potential functional synergy among these interconnected axes of cellular plasticity in enabling metastasis and multi-drug resistance in cancer.

Specific epigenetic regulators serve as potential therapeutic targets in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF), a disorder observed mostly in older human beings, is characterised by chronic and progressive lung scarring leading to an irreversible decline in lung function. This health condition has a dismal prognosis and the currently available drugs only delay but fail to reverse the progression of lung damage. Consequently, it becomes imperative to discover improved therapeutic compounds and their cellular targets to cure IPF. In this regard, a number of recent studies have targeted the epigenetic regulation by histone deacetylases (HDACs) to develop and categorise antifibrotic drugs for lungs. Therefore, this review focuses on how aberrant expression or activity of Classes I, II and III HDACs alter TGF-ß signalling to promote events such as epithelial-mesenchymal transition, differentiation of activated fibroblasts into myofibroblasts, and excess deposition of the extracellular matrix to propel lung fibrosis. Further, this study describes how certain chemical compounds or dietary changes modulate dysregulated HDACs to attenuate five faulty TGF-ß-dependent profibrotic processes, both in animal models and cell lines replicating IPF, thereby identifying promising means to treat this lung disorder.