Biology subjects

Lotan, T.

Publications and source records attributed to Lotan, T..

10 recordsLinked to original sources

bioRxiv2026

TFE3 fusions drive expression of CD44 and SPP1 in Translocation Renal Cell Carcinoma

Xp11.2 translocation RCC [Xp11.2 tRCC]) is an underdiagnosed and aggressive subtype of RCC with few specific or targeted therapies. The transmembrane glycoprotein CD44 is an emerging target in many advanced malignancies, and with its ligand OPN (SPP1), is a crucial driver of cancer progression, stemness, metastasis, and immune suppression. Here we show that common TFE3-fusions [ including SFPQ-TFE3, PRCC-TFE3, ASPSCR1-TFE3, and NONO-TFE3] are associated with upregulated expression of CD44 and SPP1, as observed in multiple human and murine bulk transcriptomic studies and a murine tRCC snRNA-Seq dataset. CD44 and/or SPP1 protein expression were also upregulated in murine models of transgenic tRCC kidneys and urine specimens, patient-derived cell lines and human tRCC cases, by immunoblotting and/or IHC. Transient deletion of CD44 was associated with profound and specific suppression of tRCC cell line growth, with decreased mTOR signaling. These data suggest that CD44 and/or SPP1 may potentially drive tumorigenesis in tRCC.

cancer biology↗

bioRxiv2024

Predation on scyphozoan polyps and selective nematocyst incorporation dynamics in the aeolid, Caloria militaris

Aeolid nudibranchs are known to prey on various cnidarians and incorporate nematocysts from their prey into their cerata (dorsal appendages) for self-defense. Nematocyst incorporation is selective, and is based on species, diet, prey availability, and predation pressure. This study investigated the interactions between two nudibranch species, Caloria militaris and Flabellina affinis, and scyphozoan polyps from common eastern Mediterranean jellyfish species, including Rhopilema nomadica, Cassiopea andromeda, Phyllorhiza punctata, and Aurelia sp. Laboratory experiments were used to assess whether these nudibranchs feed on scyphozoan polyps, and if they incorporate the prey nematocysts into the cerata. Results indicate that while F. affinis avoids scyphozoan polyps, C. militaris consumes all tested species, and can subsist on them for extended durations (up to 255 days). Predation rates varied among prey species tested, ranging from a mean of 8 to 43.3 polyps day-1. However, C. militaris does not store scyphozoan nematocysts. These findings contribute to understanding nudibranch feeding ecology and the potential roles these predators play in regulating jellyfish blooms. Identification of scyphozoan nematocysts in the cerata of predator aeolid nudibranchs is discussed as a means to locate cryptic scyphozoan polyps in the marine environment.

ecology↗

bioRxiv2024

Jellyfish blooms Through the Microbial Lens: Temporal Changes, Cross-Species and Jellyfish-Water Comparisons

In this study, we explore the dynamics of bacterial communities associated with Rhopilema nomadica blooms, the predominant jellyfish in the Eastern Mediterranean Sea. We collected over 120 samples from more than 30 individuals across five major bloom events, capturing both lesser-studied winter blooms and the peaks and declines of summer blooms. Our analysis revealed significant microbial shifts-increases in Endozoicomonas and unclassified Rickettsiales were significantly more abundance during late summer blooms, while Tenacibaculum dominated in winter. Additionally, we examined microbial patterns within specific tissues--bell, gonads, tentacles, and gastrovascular system--to assess variations across these different niches. This revealed high relative abundance of specific taxa tailored to different tissue-Bacteroides was predominantly found in the bell, Simkaniaceae in the gonads, and Endozoicomonas in the tentacles. Further expanding our research, we compared the top taxa of R. nomadica with those of nine other jellyfish species from different locations. Interestingly, while no universal core microbiome was found, several taxa, including Endozoicomonas, Mycoplasma, and Spiroplasma, were common across different species, suggesting their potential ecological roles across jellyfish. Lastly, our study of potential bacterial transmission modes revealed that key bacteria associated with R. nomadica are exclusively found near bloom areas, and are absent from remote seawater, highlighting potential localized transmission dynamics between jellyfish and their immediate marine environment. Our study marks the first exploration of microbial dynamics within R. nomadica, while also broadening the understanding of other jellyfish microbial communities and setting the stage for future studies to delve deeper into their complex interactions. IMPORTANCEJellyfish blooms, like those of Rhopilema nomadica in the Eastern Mediterranean, impact marine ecosystems and human industries. Understanding the complex relationships between jellyfish and their microbiomes is important, as these interactions may influence bloom formation and decline. Our study explores microbiome variations across different stages of R. nomadica blooms, identifies common bacteria among jellyfish from various locations, and examines potential transmission modes of the main jellyfish-associated bacteria. Microbial communities vary significantly between bloom stages and jellyfish tissues, becoming less diverse towards the end of the bloom. Although no universal core microbiome was discovered, taxa such as Endozoicomonas, Mycoplasma, and Spiroplasma are prevalent across various jellyfish, suggesting significant ecological roles. Finally, our findings indicate that key bacteria associated with R. nomadica predominantly reside near bloom areas and are absent from distant seawater, highlighting localized transmission mode. This study enhances our understanding of jellyfish-associated microbial communities and their role in bloom dynamics.

microbiology↗

bioRxiv2024

Directional swimming patterns in jellyfish aggregations

Having a profound influence on marine and coastal environments worldwide, jellyfish hold significant scientific, economic, and public interest. The predictability of outbreaks and dispersion of jellyfish is limited by a fundamental gap in our understanding of their movement. Although there is evidence that jellyfish may actively affect their position, the role of active swimming in controlling jellyfish movement, and the characteristics of jellyfish swimming behavior, are not well understood. Consequently, jellyfish are often regarded as passively drifting or randomly moving organisms, both conceptually and in process studies. Here we show that the movement of jellyfish is controlled by distinctly directional swimming patterns, which are oriented against the direction of surface gravity waves. Taking a Lagrangian viewpoint from drone videos that allows the tracking of multiple adjacent jellyfish, and focusing the scyphozoan jellyfish Rhopilema nomadica as a model organism, we show that the behavior of individual jellyfish translates into a synchronized directional swimming of the aggregation as a whole. Numerical simulations show that this counter-wave swimming behavior results in biased correlated random-walk movement patterns that reduce the risk of stranding, thus providing jellyfish with an adaptive advantage critical to their survival. Our results emphasize the importance of active swimming in regulating jellyfish movement, and open the way for a more accurate representation in model studies, thus improving the predictability of jellyfish outbreaks and their dispersion, and contributing to our ability to mitigate their possible impact on coastal infrastructure and populations.

ecology↗

bioRxiv2024

LSD1 inhibition suppresses ASCL1 and de-represses YAP1 to drive potent activity against neuroendocrine prostate cancer

Progression to lethal metastatic castration-resistant prostate cancer (mCRPC) is driven in part by epigenetic modulators such as LSD1 (KDM1A), a lysine-specific demethylase. Yet, mCRPC is increasingly recognized as a highly heterogeneous disease whose classification into subtypes is defined by the extent of androgen receptor (AR) and/or neuroendocrine (NE) characteristics. Meanwhile, the role of LSD1 in driving the different subtypes of mCRPC has remained unclear. Here, we assess the necessity of LSD1 in driving progression of mCRPC subtypes including AR+/NE- (ARPC), AR-/NE+ (NEPC), AR+/NE+ (amphicrine; AMPC), and AR-/NE- (double-negative; DNPC) through the use of LSD1 inhibitors in clinical development. LSD1 inhibition (LSD1i) was observed to be highly effective in restricting growth of NEPC, and efficacy was associated with TP53 loss-of-function. Mice bearing NEPC patient-derived xenografts treated with the LSD1 inhibitors, bomedemstat (MK-3543) or iadademstat (ORY-1001), exhibited suppression of the NE transcriptional profile, including ASCL1. LSD1i also induced expression and activity of YAP1, a non-NE transcription factor canonically silenced in NEPC (YAPOFF cancer), thereby switching NEPC from a YAPOFF to a YAPON cancer class. Therapeutically-induced YAPON NEPC tumors exhibited cell cycle arrest and repression of proliferative transcriptional programs. Importantly, the LSD1i-mediated YAPON state induced sensitivity to an inhibitor of YAP/TEAD function, IAG933, which extended antitumor efficacy against NEPC. Altogether, these findings indicate that patients diagnosed with NEPC may obtain greater relative benefit from LSD1-targeted therapies compared to those with other mCRPC subtypes and that dual inhibition of LSD1 and YAP/TEAD function demonstrates a promising treatment strategy potentially extending to other YAPOFF cancers. SignificanceAcross prostate cancer subtypes, NEPC is exceptionally responsive to LSD1 inhibition and this response is enhanced in combination with a YAP/TEAD disruptor which may improve patient selection and outcomes. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=171 HEIGHT=200 SRC="FIGDIR/small/576106v2_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@77332eorg.highwire.dtl.DTLVardef@1c127d0org.highwire.dtl.DTLVardef@1cec77org.highwire.dtl.DTLVardef@e87ed7_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

Selecting 16S rRNA primers for microbiome analysis in a host-microbe system: the case of the jellyfish Rhopilema nomadica

Amplicon sequencing of the 16S rRNA gene is extensively used to characterize bacterial communities, including those living in association with eukaryotic hosts. Deciding which region of the 16S rRNA gene to analyze and selecting the appropriate PCR primers remained a major decision when initiating any new microbiome study. Here, we compared three commonly used primers targeting different hypervariable regions of the 16S rRNA gene, V1V2, V3V4, and V4V5, using the jellyfish Rhopilema nomadica as a model. Although all primers exhibit a similar pattern in bacterial community composition, the performance of the V3V4 primer set was superior to V1V2 and V4V5. The V1V2 primers misclassified bacteria from the Bacilli class and exhibited low classification resolution for Rickettsiales, which represent the second most abundant 16S rRNA gene sequence in all the primers. The V4V5 primer set detected almost the same community composition as the V3V4, but the ability of these primers to also amplify eukaryotic 18S rRNA gene may hinder bacterial community observations. However, after overcoming the challenges possessed by each one of those primers, we found that all three of them show very similar bacterial community dynamics and composition. Nevertheless, based on our results, we propose that the V3V4 primer set is the most suitable for studying jellyfish-associated bacterial communities. Our results suggest that, at least for jellyfish samples, it may be feasible to directly compare microbial community estimates from different studies, each using different primers but otherwise similar experimental protocols. More generally, we recommend specifically testing different primers as a prelude to large-scale 16S rRNA gene amplicon analyses, especially of previously unstudied host-microbe associations.

microbiology↗

bioRxiv2021

Cellular pathways during spawning induction in the starlet sea anemone Nematostella vectensis

In cnidarians, long-term ecological success relies on sexual reproduction. The sea anemone Nematostella vectensis, which has emerged as an important model organism for developmental studies, can be induced for spawning by temperature elevation and light exposure. To uncover molecular mechanisms and pathways underlying spawning, we characterized the transcriptome of Nematostella females before and during spawning induction. We identified an array of processes involving numerous receptors, circadian clock components, cytoskeleton, and extracellular transcripts that are upregulated upon spawning induction. Concurrently, processes related to the cell cycle, fatty acid metabolism, and other housekeeping functions are downregulated. Real-time qPCR revealed that light exposure has a minor effect on expression levels of most examined transcripts, implying that temperature change is a stronger inducer for spawning in Nematostella. Our findings reveal the mechanisms that may enable the mesenteries to serve as a gonad-like tissue for the developing oocytes and expand our understanding of sexual reproduction in cnidarians. Summary statementAnalysis of transcriptional changes during spawning induction in Nematostella vectensis, revealed upregulation of processes related to signal perception and cytoskeleton rearrangement and downregulation of fatty acid metabolism and housekeeping processes.

ecology↗

bioRxiv2020

Transcriptional landscape of PTEN loss in primary prostate cancer

PTEN is the most frequently lost tumor suppressor in primary prostate cancer (PCa) and its loss is associated with aggressive disease. However, the transcriptional changes associated with PTEN loss in PCa have not been described in detail. Here, we applied a meta-analysis approach, leveraging two large PCa cohorts with experimentally validated PTEN and ERG status, to derive a transcriptomic signature of PTEN loss, while also accounting for potential confounders due to ERG rearrangements. Strikingly, the signature indicates a strong activation of both innate and adaptive immune systems upon PTEN loss, as well as an expected activation of cell-cycle genes. Moreover, we made use of our recently developed FC-R2 expression atlas to expand this signature to include many non-coding RNAs recently annotated by the FANTOM consortium. With this resource, we analyzed the TCGA-PRAD cohort, creating a comprehensive transcriptomic landscape of PTEN loss in PCa that comprises both the coding and an extensive non-coding counterpart.

cancer biology↗

bioRxiv2020

Role of Specialized mSWI/SNF Complexes in Prostate Cancer Lineage Plasticity

Advanced prostate cancer initially responds to hormonal treatment, but ultimately becomes resistant and requires more potent therapies. One mechanism of resistance observed in [~]10% of these patients is through lineage plasticity, which manifests in a partial or complete small cell or neuroendocrine prostate cancer (NEPC) phenotype. Here, we investigate the role of the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex in NEPC. Using large patient datasets, patient-derived organoids and cancer cell lines, we identify mSWI/SNF subunits that are deregulated in NEPC and demonstrate that SMARCA4 (BRG1) overexpression is associated with aggressive disease. We also show that SWI/SNF complexes interact with different lineage-specific factors in NEPC compared to prostate adenocarcinoma. These data suggest a role for mSWI/SNF complexes in therapy-related lineage plasticity, which may be relevant for other solid tumors.

cancer biology↗

bioRxiv2019

Signaling via GABAB receptors regulates early development and neurogenesis in the basal metazoan Nematostella vectensis

The metabotropic gamma-amino-butyric acid B receptor (GABABR) is a G protein-coupled receptor that mediates neuronal inhibition by the neurotransmitter GABA. Here, we identified putative GABAB receptors and signaling modulators in the basal sea anemone Nematostella vectensis. Activation of GABABR signaling reversibly arrests planula-to-polyp transformation during early development and affects the neurogenic program. We identified four Nematostella GABABR homologs that have the conserved 3D extracellular domains and residues needed for binding of GABA and the GABABR agonist baclofen. Transcriptomic analysis, combined with spatial analysis of baclofen-treated planulae, revealed that baclofen down-regulated pro-neural factors such as NvSoxB(2), NvNeuroD1 and NvElav1. Baclofen also inhibited neuron development and extended neurites, resulting in an under-developed and less organized nervous system. Our results shed light on cnidarian development and suggest an evolutionarily conserved function for GABABR in regulation of neurogenesis, highlighting Nematostella as a new model system to study GABABR signaling.

molecular biology↗