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Shaked, Y.

Publications and source records attributed to Shaked, Y..

9 recordsLinked to original sources

Active late Holocene accretion of mesophotic coral-rubble fields in the northern Red Sea

Mesophotic coral ecosystems are commonly interpreted as thin biological veneers over relict shallow-water reef structures, but their capacity to generate late Holocene carbonate deposits remains poorly quantified. Here we combine diver excavations, rubble-bed thickness surveys, radiocarbon age-depth modelling, sediment grain-size analyses, coral-rubble assemblages, trace-element geochemistry, and modern Alveopora allingi growth measurements from two 40-65 m deep coral-rubble fields in the northern Gulf of Eilat/Aqaba, Red Sea. Rubble deposits are at least 1.0-1.5 m thick and accumulated at mean rates of 2.21 {+/-} 0.52 mm yr-1 at the Dekel site and 1.33 {+/-} 0.13 mm yr-1 at the IUI site, implying persistent carbonate accumulation over centuries to >1 kyr. Age-depth models indicate quasi-continuous deposition despite pronounced faunal changes, including a shift from A. allingi-dominated rubble to upper layers enriched in Euphyllia paradivisa at Dekel. The dominant modern rubble-forming coral, A. allingi, extends at 3.04 {+/-} 0.87 mm yr-1 and has skeletal density of 1.17 {+/-} 0.27 g cm-3. First-order cover-based accretion estimates at present coral cover fall well below the radiocarbon-derived rates, indicating that long-term mesophotic rubble accumulation integrates historical cover, secondary calcification and sediment retention rather than present live coral cover alone. These data demonstrate that mesophotic rubble fields can act as active carbonate factories and palaeoecological archives, challenging the assumption that modern mesophotic habitats are geomorphologically passive.

ecology↗

The coumarin derivative X6632 is a pan-ID protein inhibitor that suppresses tumor growth by targeting cancer cells and the tumor-associated microvasculature

Inhibitor of DNA binding (ID) proteins are key regulators of tumor cell stemness, therapy resistance and pathological angiogenesis in multiple cancer types and other diseases. Here, we characterize the coumarin-derived compound X6632 as a pan-ID inhibitor with dual activity against tumor cells and the tumor-associated microvasculature in a number of human and murine models. X6632 efficiently suppressed ID protein expression, inhibited the proliferation, migration, invasion of melanoma cells, and impaired multiple endothelial cell functions, including proliferation, migration, invasion, tube formation and sprouting in vitro. In back-to-back comparisons, X6632 exhibited an approximately ten-fold higher efficacy compared to the first-generation ID antagonist AGX51. In vivo, X6632 potently reduced pathological (neo)vascularization in established angiogenesis models, including oxygen-induced retinopathy and in Matrigel plug assays. It also significantly decreased blood vessel density in syngeneic melanoma models, delayed tumor growth and, when combined with immune checkpoint blockade, achieved superior tumor control compared with either monotherapy. Moreover, X6632 inhibited clonogenic growth in several breast cancer models, and robustly suppressed the growth of triple negative breast cancer in vivo, both in the highly aggressive 4T1 syngeneic model and in patient-derived xenografts. Collectively, these data establish X6632 as a second-generation, pan-ID protein inhibitor that can simultaneously target malignant cells and the tumor-supporting vasculature, and support the further pre-clinical development of the compound for the treatment of melanoma, breast cancer and potentially additional ID-dependent malignancies, as well as diseases driven by pathological neoangiogenesis.

cancer biology↗

Reverse molecular pharmacology identifies the non-canonical axis of IRAK as a chemoresistance factor in neuroblastoma

Owing to chemoresistance, the prognosis of relapsed neuroblastoma is dismal with less than 10% of patients surviving after 5 years. We developed a reverse molecular pharmacology approach that is based on high-throughput drug screening coupled with chemo-informatic and transcriptomic analyses. This led to the identification of IRAK1 as a key chemoresistance factor in neuroblastoma. By performing functional and pharmacological drug combination screens targeting IRAK1, we revealed a synergy between IRAK1 inhibition/silencing and BET, EGFR and mTOR inhibitors as well as microtubule-targeting agents. The synergistic combination of microtubule-targeting agent, vincristine and IRAK inhibitors was then confirmed in tumor spheroids, patient-derived tumoroids and a syngeneic orthotopic mouse model. Mechanistically, IRAK inhibition potentiated the pro-apoptotic and cell cycle arrest properties of vincristine via a pathway involving the PIDDosome complex rather than its canonical MyDDosome axis. Altogether, this study represents a proof-of-concept of our reverse molecular pharmacology approach to quickly develop biology-guided drug combinations, that could be applied to any other human diseases.

cancer biology↗

Phenotypic variability between closely related Trichodesmium strains as a means to making the most out of heterogeneous microenvironments

The cynobacteria Trichodesmium spp., play an important role in oceanic carbon and nitrogen cycles. Forming colonies that host diverse microorganisms likely enhances Trichodesmiums metabolic flexibility and resilience. Combining single-colony metagenomics and metatranscriptomics with a novel bioinformatic approach we investigated the community composition and transcriptional activity of 69 individual Trichodesmium thiebautii colonies collected from the northern Red Sea, Israel. Three Trichodesmium strains were detected in all colonies, each with a heterogenous yet distinct transcriptional-activity profile. N-fixation, superoxide dismutase, and ATPase activities were similar among colonies, while P and Fe uptake, as well as photosynthesis, were high in only few colonies. Colonies had no core microbiome with >70% dissimilarity in the associated microbial communities, yet, the abundance of some species was correlated with the activity of specific Trichodesmium strains. We propose Trichodesmium occupies heterogeneous microenvironments with which it deals through inter-strain phenotypic variability further fine-tuned through interactions with beneficial, non-fixed, heterotrophic colonizers.

microbiology↗

Biological insights from plasma proteomics of non-small cell lung cancer patients treated with immunotherapy

IntroductionImmune checkpoint inhibitors have made a paradigm shift in the treatment of non-small cell lung cancer (NSCLC). However, clinical response varies widely and robust predictive biomarkers for patient stratification are lacking. Here, we characterize early on-treatment proteomic changes in blood plasma to gain a better understanding of treatment response and resistance. MethodsPre-treatment (T0) and on-treatment (T1) plasma samples were collected from 225 NSCLC patients receiving PD-1/PD-L1 inhibitor-based regimens. Plasma was profiled using aptamer-based technology to quantify approximately 7000 plasma proteins per sample. Proteins displaying significant fold changes (T1:T0) were analyzed further to identify associations with clinical outcomes. Bioinformatic analyses of upregulated proteins were performed to determine potential cell origins and enriched biological processes. ResultsThe levels of 142 proteins were significantly increased in the plasma of NSCLC patients following ICI-based treatments. Soluble PD-1 exhibited the highest increase, with a positive correlation to tumor PD-L1 status. Bioinformatic analysis of the ICI monotherapy dataset revealed a set of 30 upregulated proteins that formed a single, highly interconnected network with CD8A serving as a central hub, suggesting T cell activation during ICI treatment. Notably, the T cell-related network was detected regardless of clinical benefit. Lastly, circulating proteins of alveolar origin were identified as potential biomarkers of limited clinical benefit, possibly due to a link with cellular stress and lung damage. ConclusionsOur study provides insights into the biological processes activated during ICI-based therapy, highlighting the potential of plasma proteomics to identify mechanisms of therapy resistance and potential biomarkers for outcome.

bioinformatics↗

Taxonomic distribution of metabolic functions underpin nutrient cycling in Trichodesmium consortia

The photosynthetic and diazotrophic cyanobacterium Trichodesmium is a key contributor to marine biogeochemical cycles in the subtropical-oligotrophic oceans. Trichodesmium forms colonies that harbor a distinct microbial community, which expands their functional potential and is predicted to influence the cycling of carbon, nitrogen, phosphorus and iron (C, N, P, and Fe). To link key traits to taxa and elucidate how community structure influences nutrient cycling, we assessed Red Sea Trichodesmium colonies using metagenomics and metaproteomics. This diverse consortium comprises bacteria that typically associate with algae and particles, such as the ubiquitous Alteromonas macleodii, but also lineages specific to Trichodesmium, such as members from the order Balneolales. These bacteria carry functional traits that would influence resource cycling in the consortium, including siderophore biosynthesis, reduced phosphorus metabolism, vitamins, denitrification, and dissimilatory-nitrate-reduction-to-ammonium (DNRA) pathways. Denitrification and DNRA appeared to be modular as bacteria collectively completed the steps for these pathways. The vast majority of associated bacteria were auxotrophic for vitamins, indicating the interdependency of consortium members. Trichodesmium in turn may rely on associated bacteria to meet its high Fe demand as several lineages can synthesize the photolabile siderophores vibrioferrin, rhizoferrin, and petrobactin, enhancing the bioavailability of particulate-Fe to the entire consortium. Our results highlight that Trichodesmium is a hotspot for C, N, P, Fe, and vitamin exchange. The functional redundancy of nutrient cycling in the consortium likely underpins its resilience within an ever-changing global environment. ImportanceColonies of the cyanobacteria Trichodesmium act as a biological hotspot for the usage and recycling of key resources such as C, N, P and Fe within an otherwise oligotrophic environment. While Trichodesmium colonies are known to interact with a unique community of algae and particle-associated microbes, our understanding of the taxa that populate these colonies and the gene functions they encode is still limited. Characterizing the taxa and adaptive strategies that influence consortium physiology and its concomitant biogeochemistry is critical in a future ocean predicted to have increasing particulate fluxes and resource-depleted regions.

microbiology↗

Metagenomes of Red Sea subpopulations challenge the use of morphology and marker genes to assess Trichodesmium diversity

The bloom forming Trichodesmium are filamentous cyanobacteria of key interest due to their ability to fix carbon and nitrogen within an oligotrophic marine environment. Trichodesmium blooms typically comprise a complex assemblage of subpopulations and colony-morphologies that are predicted to exhibit distinct ecological lifestyles. Here, we assessed the poorly studied diversity of Trichodesmium in the Red Sea, based on metagenome-assembled genomes (MAGs) and hetR gene-based phylotyping. We assembled four non-redundant MAGs from morphologically distinct Trichodesmium colonies (tufts, dense and thin puffs). T. thiebautii (puffs) and T. erythraeum (tufts) were the dominant species within these morphotypes. While subspecies diversity is present for both T. thiebautii and T. erythraeum, a single T. thiebautii genotype comprised both thin and dense puff morphotypes, and we therefore hypothesize that the phenotypic variation between these morphologies is likely attributed to gene regulation. Additionally, we found the rare non-diazotrophic clade IV and V genotypes, related to T. nobis and T. miru respectively, that likely occurred as single filaments. HetR gene phylogeny indicates that the genotype in clade IV could represent the species T. contortum. We further show that hetR phylotyping can overestimate the taxonomic diversity of Trichodesmium, as two copies of the hetR gene were present within T. thiebautii genomes, one of which misidentified this lineage as T. aureum. Taken together, our results highlight the importance of re-assessing Trichodesmium taxonomy while showing the ability of genomics to capture the complex diversity and distribution of Trichodesmium populations.

microbiology↗

Metronomic therapy prevents emergence of drug resistance by maintaining the dynamic of intratumor heterogeneity.

Despite recent advances in deciphering cancer drug resistance mechanisms, relapse is a widely observed phenomenon in advanced cancers, mainly due to intratumor clonal heterogeneity. How tumor clones progress and impact each other remains elusive. By better understanding clone dynamics, we could reveal valuable biological insights and unveil vulnerabilities that could be therapeutically exploited. In this study, we developed 2D and 3D non-small cell lung cancer co-culture systems and defined a phenomenological mathematical model. Our results demonstrated a dominant role of the drug-sensitive clones over the drug-resistant ones under untreated conditions. Model predictions and their experimental in vitro and in vivo validations indicated that metronomic schedule leads to a better regulation of tumor cell heterogeneity over time than maximum-tolerated dose schedule, while achieving control of global tumor progression. We finally showed that drug-sensitive clones exert a suppressive effect on the proliferation of the drug-resistant ones through a paracrine mechanism way, which is linked to metabolic cell clone activity. Altogether, these computational and experimental approaches allow assessment of drug schedules controlling drug-sensitive and -resistant clone balance and highlight the potential of targeting cell metabolism to manage intratumor heterogeneity. SignificanceCombined computational and experimental models reveal how drug-sensitive tumor cells exert their dominance over drug-resistant cells and how it impacts optimal chemotherapy scheduling.

cancer biology↗

Tumor-educated uncommitted hematopoietic stem cells promote a metastatic switch

Myeloid skewing of hematopoietic cells is a prominent promoter of metastasis. However, little is known about their education and differentiation pattern from hematopoietic stem and progenitor cells (HSPCs) during tumor progression and metastasis. Here we show that metastatic tumors dictate a unique differentiation pattern of HSPCs towards a specific myeloid progeny. Using single cell RNA-sequencing analysis integrated with proteomic screen of tumor secretome, we demonstrate that highly metastatic tumors dictate a long-lived differentiation of HSPCs towards monocyte-dendritic progenitors (MDPs) while low-metastatic tumors promote their differentiation into granulocyte-monocyte progenitors (GMPs). This effect is driven by IL-6 axis that is highly active in metastatic tumors. Consequently, loss and gain of function of IL-6 in tumor cells resulted in decreased and increased metastasis and corresponding MDP levels, respectively. Consistently, IL-6-educated MDPs but not GMPs obtained from highly metastatic tumors, adoptively transferred into mice bearing low metastatic tumors resulted in increased metastasis due to their further differentiation into immunosuppressive (M2) macrophages. Overall, our study reveals a new role for tumor-derived IL-6 that hijacks HSPC differentiation program towards myeloid cells that contribute to metastasis.

cancer biology↗