Biology subjects

Steele, R. E.

Publications and source records attributed to Steele, R. E..

5 recordsLinked to original sources

bioRxiv2025

NNMT is a biomarker of prostate cancer cells with a mesenchymal phenotype and induces sensitivity to metabolic agents

Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD+ salvage pathway and a promising therapeutic target in cancer. Resistance to NAMPT inhibitors, such as FK866, remains a key limitation to their clinical translation. While acquired resistance in cancer cell lines has been linked to target mutations, increased drug efflux and metabolic reprogramming, innate resistance mechanisms have been poorly studied. Addressing this gap is essential for identifying patient subgroups most likely to benefit from NAMPT-targeted therapies. Advanced castration resistance prostate cancer (CRPC) lacks effective targeted treatments. Among its heterogeneous subtypes, stem cell-like CRPC (CRPC-SCL) is defined by androgen receptor (AR) independence, YAP/TAZ dependency, and mesenchymal traits. In this study, we identify the YAP/nicotinamide N-methyltransferase (NNMT) axis as a key mediator of innate sensitivity to FK866 in stem-like mesenchymal CRPC cells. Using genetic and pharmacological models, we show that YAP or NNMT silencing rescues mesenchymal CRPC cells from FK866-induced apoptosis, endoplasmic reticulum stress, and NAD(H) loss. Metabolomic profiling confirmed that NNMT activity depletes nicotinamide, sensitizing cells to FK866. We further validated NNMT upregulation across clinical CRPC- SCL datasets, where it strongly correlates with mesenchymal and therapy-resistant phenotypes, as well as in murine prostate cancer cells with mesenchymal/stemness phenotypes. In conclusion, we identify the YAP/NNMT axis as a determinant of innate sensitivity to NAMPT inhibition in prostate cancer. These findings support the use of NNMT as a predictive biomarker for NAD+-targeting therapies and provide mechanistic insight into a metabolic vulnerability of the CRPC-SCL subtype. Targeting the YAP/NNMT/NAMPT axis may represent a novel strategy for treating stem-like/mesenchymal, therapy-resistant prostate cancers. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/651153v2_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@de4237org.highwire.dtl.DTLVardef@1cd577corg.highwire.dtl.DTLVardef@2aa97corg.highwire.dtl.DTLVardef@dd2ac0_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

The dynamic genomes of Hydra and the anciently active repeat complement of animal chromosomes

Many animal genomes are characterized by highly conserved chromosomal homologies that pre-date the ancient origin of this clade. Despite such conservation, the evolutionary forces behind the retention, expansion, and contraction of chromosomal elements, and the resulting macro-evolutionary implications, are unknown. Here we present a comprehensive stem-cell resolved genomic and transcriptomic study of the fresh-water cnidarian Hydra, an animal characterized by its high regenerative capacity, the ability to propagate clonally, and an apparent lack of aging. Using single-haplotype telomere-to-telomere genome assemblies of two recently diverged hydra strains, we show how the macro-evolutionary history of chromosomal elements is shaped by both old and recent transposable element (TE) expansions. Unique features of hydra biology allowed us to compare the individual genomes of hydras three stem cell lineages. We show that distinct TE families are active at both transcriptional and genomic levels via non-random insertions in the genomes of each of these lineages. In transcriptomes, over 14,000 transcripts were composed of nearly complete TE sequences, and further classification into families, subfamilies, and individual loci reveals cell type-specific TE expression. The active TEs include elements that differentially contribute to changes in the genome size as well as persistent structural variants around loci associated with cell proliferation. Our study reveals 14 active TE families that primarily act in this role and are predominantly composed of DNA elements. Evolutionary analysis revealed that these families constitute a highly conserved TE core in eukaryotic and metazoan genomes. Our results suggest an ancient role for these core TEs as self-renewing genomic components that persist beyond ancient chromosomal homologies.

genomics↗

bioRxiv2022

Coevolution of the Tlx homeobox gene with medusa development (Cnidaria: Medusozoa)

The jellyfish, or medusa, is a life cycle stage characteristic of the cnidarian subphylum Medusozoa. By contrast, the other cnidarian subphyla Anthozoa and Endocnidozoa lack a medusa stage. Of the medusozoan classes, Hydrozoa is the most diverse in terms of species number and life cycle variation. A notable pattern in hydrozoan evolution is that the medusa stage has been lost or reduced several times independently. Although this loss of the jellyfish stage is thought to be due to heterochrony, the precise developmental mechanisms underlying this complex pattern of medusa evolution are unknown. We found that the presence of the homeobox gene Tlx in cnidarian genomes is correlated with those medusozoans that have a medusa stage as part of their life cycle. Although Tlx is conserved in Bilateria and Cnidaria, it is missing in the genomes of anthozoans, endocnidozoans, and those hydrozoans that have lost the medusa stage. Selection analyses of Tlx across medusozoans revealed that hydrozoans undergo relatively relaxed selection compared to the other medusozoan classes, which may in part explain the pattern of multiple medusa losses. Differential expression analyses on three distantly related medusozoan representatives indicate an upregulation of Tlx during medusa development. In addition, Tlx expression is spatially restricted to regions of active development in medusae of the hydrozoan Podocoryna carnea. Our results suggest that Tlx plays a key role in medusa development and that the loss of this gene is likely linked to the repeated loss of the medusa life cycle stage.

evolutionary biology↗

bioRxiv2019

Ancestral role of Fat-like cadherins in planar cell polarity

Fat family cadherins are enormous proteins that regulate planar cell polarity (PCP) and cell adhesion in bilaterian animals. Their evolutionary origin can be traced back to prebilaterian species, but their ancestral function(s) are unknown. We identified Fat-like and Dachsous cadherins in Hydra, a member of the early-diverging metazoan phylum Cnidaria. Hydra has a simple body plan with only two epithelial layers and radial symmetry. We find that Hydra homologues of Fat-like (HyFat) and Dachsous (HyDs) co-localize at the apico-lateral membrane of ectodermal epithelial cells. Remarkably, HyFat is planar polarized perpendicular to the oral-aboral axis of the animal. Using knockdown approaches we found that HyFat is involved in the regulation of local cell alignment, but is dispensable for the global alignment of ectodermal myonemes along the oral-aboral axis. The intracellular domain (ICD) of HyFat is involved in the morphogenesis of ectodermal myonemes. Thus, Fat family cadherins have ancient, prebilaterian functions in cell adhesion, tissue organization and planar polarity.

developmental biology↗

bioRxiv2017

Forces driving cell sorting in Hydra

Cell sorting, whereby a heterogeneous cell mixture organizes into distinct tissues, is a fundamental patterning process in development. So far, most studies of cell sorting have relied either on 2-dimensional cellular aggregates, in vitro situations that do not have a direct counterpart in vivo, or were focused on the properties of single cells. Here, we report the first multiscale experimental study on 3-dimensional regenerating Hydra aggregates, capable of reforming a full animal. By quantifying the kinematics of single cell and whole aggregate behaviors, we show that no differences in cell motility exist among cell types and that sorting dynamics follow a power law. Moreover, we measure the physical properties of separated tissues and determine their viscosities and surface tensions. Based on our experimental results and numerical simulations, we conclude that tissue interfacial tensions are sufficient to explain Hydra cell sorting. Doing so, we illustrate DArcy Thompsons central idea that biological organization can be understood through physical principles, an idea which is currently re-shaping the field of developmental biology.\n\nSummary statementHydra regenerates after dissociation into single cells. We show how physical mechanisms can explain the first step of regeneration, whereby ectodermal and endodermal cells sort out to form distinct tissue layers.

biophysics↗