Biology subjects

Oren, M.

Publications and source records attributed to Oren, M..

10 recordsLinked to original sources

bioRxiv2025

GLYATL1 is associated with metabolic and epigenetic changes and with endocrine resistance in luminal breast cancer

Estrogen receptor alpha (ER)-positive luminal breast cancer is commonly treated with aromatase inhibitors (AI) to block estrogen signaling; however, resistance frequently develops, limiting therapy success. We observed that GLYATL1 (Glycine-N-Acyltransferase Like 1) expression is upregulated in AI-resistant breast cancer cell models and in patients undergoing AI therapy, correlating with poorer survival. Here we demonstrate that GLYATL1 promotes resistance to estrogen deprivation by elevating succinate levels and altering epigenetic histone marks associated with active transcription. Knockdown or knockout of GLYATL1 reverses these effects and reduces proliferation under estrogen-deprived conditions. Notably, GLYATL1 expression is positively regulated by estrogen receptor alpha signaling independently of estrogen. These findings reveal GLYATL1 as a metabolic and epigenetic mediator of endocrine therapy resistance, suggesting it as a potential target to overcome AI resistance in luminal breast cancer.

cancer biology↗

bioRxiv2025

Sensitizing Immune-Refractory Ovarian Tumors via p53 Mutation-Tailored Immunotherapy

High-grade serous ovarian cancer demonstrates limited responsiveness to immune checkpoint inhibitors, owing in part to immunosuppressive environments shaped by nearly universal p53 aberrations. Utilizing an immunocompetent mouse model and individual p53 mutations, we identified a dependence of the p53-R270H mutation (equivalent of human R273H) on regulatory T cells (Tregs) and the PD-1/PD-L1 axis. Analysis of patient datasets associated R273H with elevated levels of two p53 targets, PD-L1 and amphiregulin (AREG), a Tregs growth factor. In contrast to p53-R172H tumors, where there was limited activity, dual antibody therapy targeting AREG and PD-L1 selectively and effectively inhibited R270H tumors. This involved polarization toward M1 macrophages, infiltration of CD8+ T cells, diminished Ly6G+ neutrophils and downregulation of interleukin-4. In patient-derived R273C organoids, the combination treatment reduced the CD4/CD8 ratio. This study is the first to establish a mutation-tailored therapeutic approach that leverages the capacity of p53 to modulate immunosuppressive mechanisms.

cancer biology↗

bioRxiv2024

Differential colonization and succession dynamics of marine bacteria on different plastic polymers

During the past decades since plastic was introduced to the world, marine microorganisms have been adapted for life on marine plastic debris, forming unique plastic-attached microbial communities. To date, little is known about the colonization and succession processes that take place on plastic surfaces in marine environments and how the plastic polymer type affects the plastic-attached microbiome composition. To address this knowledge gap, we examined the colonization and succession dynamics of marine bacteria on four common plastic polymers - PE, PP, PS, and PET-compared to glass and wood in a controlled seawater system under different temperatures. Using a simple experimental design, coupled with a long-read 16S rRNA metabarcoding pipeline and a set of complementary data analyses, we characterized the temporal trends in the composition of the bacterial microbiome developed on different surfaces over 2 - 90 days. By applying weighted gene co-expression network (WGCNA) analysis, we established co-occurrence networks and identified genera with specific succession signatures, significant enrichment on specific plastic polymers and/or strong intra-genus connections. Among them, members of genus Alcanivorax were significantly enriched on either PE or PP plastic surfaces as early as 2 days post-inoculation. Alcanivorax colonization preference to polyolefins was confirmed in colonization assays with pure Alcanivorax strains. Our research approach presented here may contribute to understanding how plastisphere communities are being formed and help identify taxa with specific adaptations to plastic surfaces.

ecology↗

bioRxiv2023

Characterization of novel fungal-algal symbiosis on LDPE plastic surfaces in the Mediterranean Sea

Plastic debris in the ocean serves as a stable ground for the formation of a complex ecosystem, termed plastisphere, which includes a variety of organisms from different taxonomic groups. Not much is known about the relationships between the organisms of the plastisphere communities. In this study we describe a novel symbiotic relationship between a marine fungus and several species of diatoms on plastic surfaces that were submerged in the water of a Mediterranean Sea marina in Israel. Scanning electron microscope images of the surfaces revealed a network of fungal hyphae with multiple diatom cells attached to them via the side or the tip of their body. Using DNA metabarcoding for the fungal Internal Transcribed Spacer (ITS) barcode locus, we found that the symbiotic fungus belongs to the phylum Ascomycota, and that it is more abundant on low density polyethylene (LDPE) surfaces compared to other plastic polymers and glass. We hypothesize that the observed symbiotic relationship may have mutual benefits for both parties, including surface-anchoring for the diatoms and nutritional benefits for the fungus, that reflects a recent adaptation for life on floating plastic debris.

microbiology↗

bioRxiv2022

Deciphering the involvement of the Hippo pathway co-regulators, YAP/TAZ in invadopodia formation and matrix degradation

Invadopodia are adhesive, actin-rich protrusions, formed by metastatic cancer cells that degrade the extracellular matrix and facilitate invasion. They support the metastatic cascade by a spatially and temporally coordinated process whereby invading cells bind to the matrix, degrade it by specific metalloproteinases, and mechanically penetrate diverse tissue barriers by forming actin-rich extensions. However, despite the apparent involvement of invadopodia in the metastatic process, the molecular mechanisms that regulate invadopodia formation and function are still largely unclear. In this study, we have explored the involvement of the key Hippo pathway co-regulators, namely YAP, and TAZ, in invadopodia formation and matrix degradation. Towards that goal, we tested the effect of depletion of YAP, TAZ, or both on invadopodia formation and activity in multiple human cancer cell lines. We report that knockdown of YAP and TAZ or their inhibition by verteporfin induce a significant elevation in matrix degradation and invadopodia formation in several cancer cell lines. Conversely, overexpression of these proteins strongly suppresses invadopodia formation and matrix degradation. Proteomic and transcriptomic profiling of MDA-MB-231 cells, following co-knockdown of YAP and TAZ, revealed a significant change in the levels of key invadopodia-associated proteins, including the crucial proteins Tks5 and MT1-MMP (MMP14). Collectively, our findings show that YAP and TAZ act as negative regulators of invadopodia formation in diverse cancer lines, most likely by reducing the levels of essential invadopodia components. Dissecting the molecular mechanisms of invadopodia formation in cancer invasion may eventually reveal novel targets for therapeutic applications against invasive cancer.

cancer biology↗

bioRxiv2022

Genome-wide CRISPR screens identify novel regulators of wild-type and mutant p53 stability

Tumour suppressor p53 (TP53) is the most frequently mutated gene in cancer. Several hotspot p53 mutants not only lose tumour suppressive capabilities, but also function in a dominant-negative manner, suppressing canonical wild-type p53 function. Furthermore, some hotspot p53 mutants promote oncogenesis by gain-of-function mechanisms. Levels of p53 are regulated predominantly through regulation of protein stability and while wild-type p53 is normally kept at very low levels at steady-state, p53 mutants are often stabilized in tumours, which may be vital for their oncogenic properties. Here, we systematically profiled the factors that regulate protein stability of wild-type and mutant p53 using marker-based genome-wide CRISPR screens. We found that most proteins that regulate wild-type p53 also regulate a subset of p53 mutants with the exception of p53 R337H regulators, which are largely private to this mutant. Mechanistically, we identified FBXO42 as a novel positive regulator of a subset of p53 mutants comprising R273H, R248Q and R248W. We show that FBXO42 acts together with CCDC6 to regulate USP28-mediated p53 stabilization. Our work also identifies C16orf72 as a negative regulator of the stability of wild-type p53 and of all p53 mutants tested. C16orf72 is amplified in breast cancer, and we show that C16orf72 regulates p53 levels in mammary epithelium of mice and its overexpression results in accelerated breast cancer with reduced p53 levels. Together, this work provides a network view of the processes that regulate p53 stability, which might provide clues for reinforcing wild-type p53 or targeting mutant p53 in cancer.

cancer biology↗

bioRxiv2021

High-resolution screening for marine prokaryotic and eukaryotic taxa with selective preference for PE and PET surfaces

Marine plastic debris serve as substrates for the colonization of a variety of prokaryote and eukaryote organisms. Of particular interest are the microorganisms that have adapted to thrive on plastic as they may contain genes, enzymes or pathways involved in the colonization or metabolism of plastics. We implemented DNA metabarcoding with nanopore MinION sequencing to compare the one-month-old biomes of hydrolysable (polyethylene terephthalate) and non-hydrolysable (polyethylene) plastics surfaces vs. those of glass and the surrounding water in a Mediterranean Sea marina. We sequenced longer 16S rRNA, 18S rRNA and ITS barcode loci for a more comprehensive taxonomic profiling of the bacterial, protist and fungal communities respectively. Long read sequencing enabled high-resolution mapping to genera and species. Using differential abundance screening we identified 32 bacteria and five eukaryotic species, that were differentially abundant on plastic compared to glass. This approach may be used in the future to characterize the plastisphere communities and to screen for microorganisms with a plastic-metabolism potential.

microbiology↗

bioRxiv2021

Pseudo-mutant p53 as a targetable phenotype of DNMT3A-mutated pre-leukemia

Pre-leukemic clones carrying DNMT3A mutations have a selective advantage and an inherent chemo-resistance, however the basis for this phenotype has not been fully elucidated. Mutations affecting the gene TP53 occur in pre-leukemic hematopoietic stem/progenitor cells (preL-HSPCs) and lead to chemo-resistance. Many of these mutations cause a conformational change and some of them were shown to enhance self-renewal capacity of preL-HSPCs. Intriguingly, a misfolded p53 was described in AML blasts that do not harbor mutations in TP53, emphasizing the dynamic equilibrium between a wild-type (WT) and a "pseudomutant" conformations of p53. By combining single cell analyses and p53 conformation-specific monoclonal antibodies we studied preL-HSPCs from primary human DNMT3A AML samples. We found that while leukemic blasts express mainly the WT conformation, in preL-HSPCs the pseudomutant conformation is the dominant. HSPCs from non-leukemic samples expressed both conformations to a similar extent. Treatment with a short peptide that can shift the dynamic equilibrium favoring the WT conformation of p53, specifically eliminated preL-HSPCs that had dysfunctional canonical p53 pathway activity as reflected by single cell RNA sequencing. Our observations shed light upon a possible targetable p53 dysfunction in human preL-HSPCs carrying DNMT3A mutations. This opens new avenues for leukemia prevention.

cancer biology↗

bioRxiv2020

Transcriptional profiling reveals a subset of human breast tumors that retain wt TP53 but display mutant p53-associated features

TP53 gene mutations are very common in human cancer. While such mutations abrogate the tumor suppressive activities of the wild type (wt) p53 protein, some of them also endow the mutant protein with oncogenic gain-of-function (GOF), facilitating cancer progression. Yet, p53 may acquire altered functionality even without being mutated; in particular, experiments with cultured cells revealed that wt p53 can be rewired to adopt mutant-like features in response to growth factors or cancer-mimicking genetic manipulations. To assess whether such rewiring also occurs in human tumors, we interrogated gene expression profiles and pathway deregulation patterns in the METABRIC breast cancer (BC) dataset as a function of TP53 gene mutation status. Harnessing the power of machine learning, we optimized a gene expression classifier for ER+Her2- patients that distinguishes tumors carrying TP53 mutations from those retaining wt TP53. Interestingly, a small subset of wt TP53 tumors displayed gene expression and pathway deregulation patterns markedly similar to those of TP53-mutated tumors. Moreover, similar to TP53 mutated tumors, these "pseudomutant" cases displayed a signature for enhanced proliferation and had worse prognosis than typical wt p53 tumors. Notably, these tumors revealed upregulation of genes which, in BC cell lines, were reported to be positively regulated by p53 GOF mutants. Thus, such tumors may benefit from mutant p53-associated activities without having to accrue TP53 mutations.

cancer biology↗

bioRxiv2020

Division of labor between YAP and TAZ in non-small cell lung cancer

Lung cancer is the leading cause of cancer-related deaths worldwide. The paralogous transcriptional cofactors Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ, also called WWTR1), the main downstream effectors of the Hippo signal transduction pathway, are emerging as pivotal determinants of malignancy in lung cancer. Traditionally, studies have tended to consider YAP and TAZ as functionally redundant transcriptional cofactors, with similar biological impact. However, there is growing evidence that each of them also possesses distinct attributes. Here, we sought to systematically characterize the division of labor between YAP and TAZ in non-small cell lung cancer (NSCLC), the most common histological subtype of lung cancer. Employing representative NSCLC cell lines, as well as patient-derived data, we show that the two paralogs orchestrate non-overlapping transcription programs in this cancer type: whereas YAP preferentially regulates gene sets associated with cell division and cell cycle progression, TAZ preferentially regulates genes associated with extracellular matrix organization. Concordantly, depletion of YAP, but not TAZ, leads to growth arrest, while YAP overexpression promotes cell proliferation. Likewise, depletion of TAZ, but not YAP, compromises cell migration, whereas TAZ overexpression enhances migration. Importantly, the differential effects of YAP vs TAZ on key cellular processes are also associated with differential response to anti-cancer therapies. Uncovering the different activities and downstream effects of YAP and TAZ may thus facilitate better stratification of lung cancer patients for anti-cancer therapies.

cancer biology↗