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Despite increasing interest, there remain limited treatments for chronic pain, with opioids continuing to be one of the top prescribed medications. Marine natural products present a wealth of untapped potential for new treatments for chronic pain. In this study, we investigated the analgesic effects of the sea sponge ligand barettin in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN). Barettin exhibited efficacious antihyperalgesic activity in male mice with no efficacy shown in females. Through the use of a PRESTO-Tango assay, we found that barettin acts as an inverse agonist at the 5HT2A receptor while also presenting no activity at the mu-opioid receptor. Head twitch experiments confirmed no hallucinogenic activity, suggesting that barettin may be a promising nonopioid, nonhallucinogenic, marine-derived therapeutic agent for the treatment of chronic pain.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy with few therapeutic options. Topoisomerase II alpha (TOPO2 alpha) is frequently overexpressed in PDAC and is associated with poor clinical outcomes, yet current TOPO2 alpha-directed therapies are constrained by limited efficacy and toxicity. Barettin, a brominated indole-containing diketopiperazine isolated from the marine sponge Geodia barretti, has not previously been evaluated against PDAC-relevant targets. Here, we identify barettin as a TOPO2 alpha inhibitor using an integrated phenotypic, computational, and biochemical approach. Barettin exerts a cytostatic, non-toxic effect, selectively suppressing proliferation in a subset of PDAC models while showing reduced activity in others, revealing context-dependent efficacy and biological selectivity. Consistent with this, barettin inhibits TOPO2 alpha-mediated DNA decatenation in vitro, demonstrating direct interference with enzyme activity. These findings support barettin as a selective inhibitor of a cancer-relevant proliferative pathway, uncovering a potential vulnerability in a subset of PDAC.

Marine sponges are the source of numerous bioactive natural products that serve as chemical defenses and provide pharmaceutical leads for drug development. For some of the compounds, symbiotic bacteria have been established as the actual producers. Among the known sponge symbionts, 'Candidatus Entotheonella' members stand out because of their abundant and variable biosynthetic gene clusters (BGCs). Here, to obtain broader insights into this producer taxon, we conduct a comparative analysis on eight sponges through metagenomic and single-bacterial sequencing and biochemical studies. The data suggest sets of biosynthetic genes that are largely unique in 14 'Entotheonella' candidate species and a member of a sister lineage named 'Candidatus Proxinella'. Four biosynthetic loci were linked in silico or experimentally to cytotoxins, antibiotics and the terpene cembrene A from corals. The results support widespread and diverse bacterial roles in the chemistry of sponges and aid the development of sustainable production methods for sponge-derived therapeutics.

Sponges (Porifera) are ecosystem engineers that play a critical role in global biogeochemical processes. Their evolution is key to understanding Neoproterozoic paleoecology but remains mired in controversy. Molecular timescales suggest a Tonian or Cryogenian origin, while their oldest unequivocal fossils consist of disarticulated siliceous spicules from the Late Ediacaran. We derived a new, dated sponge phylogeny and tested whether ancestral sponges had mineralized skeletons. We resolve the sponge phylogeny in good agreement with current knowledge and date their origin to the early Ediacaran. Our results suggest that early sponges were not biomineralized and that both biosilicification and biocalcification evolved independently multiple times across Porifera. We reconcile fossil evidence and molecular estimates of sponge evolution by showing that the Neoproterozoic history of Porifera is limited to the Ediacaran and providing evidence suggesting that sponges are largely absent from the Ediacaran record because they were yet to evolve biomineralized skeletons.

Demosponges (phylum Porifera) are among the first multicellular organisms on the planet and represent a unique archive of biosilica-based skeletal structures with species-specific microstructures called spicules. With more than 80 morphotypes, this class of sponges is recognized as a unique source of amorphous silica with superficial ornamentation patterned by organic phases. In this study, we investigated spicules of selected representatives of the family Geodiidae (order Tetractinellida), to identify F-actin-containing axial filaments within these 3D skeletal microconstructs defined as oxyspherasters and sterrasters. Their desilicification using 10% HF leads to isolation of multifilamentous, radially oriented organic matrices, which resemble the shape and size of the original spicules. Our data show that highly specific indicators of F-actin such as iFluorTM 594-Phalloidin, iFluorTM 488-Phalloidin, as well as iFluorTM 350-Phalloidin unambiguously confirm its localization within demineralized oxyspherasters and sterrasters of 11 diverse demosponges species belonging to the subfamily Geodiinae (genera Geodia, Rhabdastrella) and the subfamily Erylinae (genera Caminella, Caminus, Erylus, Pachymatisma). Well-defined periodicity in Geodia cydonium sterrasters actin filaments has been observed using atomic force microscopy (AFM) for the first time. The findings of F-actin as a possible pattern driver in spicules of geodiids brings additional light to our knowledge of spiculogenesis in this group. However, no specific actin structures were found between the geodiid subfamilies or genera thereby suggesting a common actin process, present already at the emergence of the family (similar to 170 million years ago).

Putative metazoan body fossils from the Precambrian are curiously lacking morphological characteristics that link them unambiguously to extant animal phyla, including sponges. Chemical fossils such as the rare C₃₀ hydrocarbons 24-iso-propylcholestane (24-ipc) and 26-methylstigmastane (26-mes), however, have been proposed as evidence for the Neoproterozoic emergence of the Demospongiae (Porifera) due to their prevalence in rocks of this age and the occurrence of their sterol precursors in contemporary demosponges. However, there are alternative hypotheses which posit that diagenetic alteration products of algal sterols, or those from Rhizaria or other protists, account for the enigmatic steroid distributions observed in these ancient sedimentary rocks. Here, we report additional support for the Neoproterozoic rise of demosponges through the chemical characterization of two previously unrecognized C₃₁ hydrocarbons—24-n-butylcholestane (24-nbc) and 24-sec-butylcholestane (24-secbc). Precursor C₃₁ sterols from contemporary demosponges, as well as a suite of synthesized C₃₁ sterol standards were reduced to their sterane counterparts. Gas chromatography-tandem mass spectrometry analysis and collisionally activated dissociation mass spectra confirmed the presence of 24-nbc and 24-secbc in well-preserved early Ediacaran rocks, and the coelution of these compounds with synthetic standards enhances the robustness of these findings. Co-occurrence of abundant 24-ipc and 24-secbc was found for numerous Neoproterozoic-Cambrian rock/oil samples, closely mimicking the abundance patterns and high structural selectivity of major C₃₀ and C₃₁ sterols detected in numerous species of modern demosponges. These findings support the hypothesized first emergence of sponges during the Neoproterozoic Era.

Geodia hentscheli, a species forming sponge grounds in the North Atlantic and Arctic Oceans, is a common deep-sea organism, that plays a fundamental role in forming biogenic habitats. However, there is little information about gene flow and adaptation patterns of this species, which is crucial to develop effective management/conservation plans under current global change scenarios. Here, we generated ddRADseq data from 110 specimens of G. hentscheli, together with microbial profiling, transcriptomics, and metatranscriptomics for a selection of specimens to investigate their genetic diversity, molecular connectivity, and local adaptations. Sampling covered the species' entire distribution within a wide bathymetric range. We obtained 1,115 neutral SNPs and identified long-distance genetic connectivity among regions separated 1,000s of km, but strong genetic structure segregating populations by depth at ca. 1,300 m, in line with our microbial analyses. Coalescent analyses inferred the split of these depth-related genetic entities ∼ 10 KYA, coincident with the last postglacial maximum. Analyses of SNPs under selection, combined with transcriptomic and metatranscriptomic data highlight the presence of several sponge genes and microbial metabolic pathways involved in adaptation to depth, including heat shock proteins and fatty acids, among others. The physiological plasticity of the sponge and its microbiome as a function of depth suggest the existence of a host-microbiome metabolic compensation for G. hentscheli. This study provides a multiscale paradigmatic example of the depth-differentiation hypothesis, a phenomenon mainly caused by changes in environmental conditions at different depths, mainly related to the presence of water masses with different characteristics that drive local adaptations.

Among the eight types of development in sponges, the least common and least studied is direct, non-larval development during viviparity. To supplement our knowledge of this rare type of demosponge development, we present here a description of the embryonic development of four species of the genus Craniella (Demospongiae, order Tetractinellida) from the deep-sea in the Northeast Atlantic. Craniella development is asynchronous within one sponge. Mature oocytes are polylecithal and isolecithal. Embryonic development occurs in a dense double-layer follicle: layers of flattened cells and a thick layer of collagen. The cleavage is total, unequal, and asynchronous. It is characterized by collagen layers penetrating inside the embryo and surrounding blastomeres. As a result of cleavage, an oval-shaped apolar stereoblastula is formed. At the stereoblastula stage, embryonic sclerocytes secrete the first megascleres, long thin oxeas, radially positioned. Later, the embryo is divided into the peripheral, intermediate, and central zones. In the intermediate zone, choanocyte chambers, lacunes, and canals of the aquiferous system are formed. The fully formed juveniles have a subspherical to flattened shape with cone-shaped outgrowths on the surface. Unlike the adults, juveniles lack cortical microxeas and have characteristic anamonaenes spicules. The juveniles exit the mother's body through the exhalant canals of the aquiferous system.

Marine sponges are among the oldest animals to have emerged on Earth. They are metazoan holobionts that host diverse microbial symbionts, which constitute more than 40% of their biomass. Despite their morphological simplicity, sponges exhibit complex genetic architecture, unquestionably encoding ribosomally synthesised and post-translationally modified peptides (RiPPs) and proteins, essential for their biological functions. In addition to host-derived compounds, the associated microbiota also produce RiPPs, introducing further complexity in distinguishing the origin of these molecules. To date, marine sponge RiPPs research is confined to species within the class Demospongiae, with peptidomic, transcriptomic and genomic approaches employed for their discovery. This review provides a comprehensive account of current research on ribosomal peptides in marine sponges and associated microsymbionts, emphasising the need for expanded discovery efforts. Unravelling the genetic basis and biosynthetic pathways of these peptides will deepen our understanding of sponge biology and open new opportunities for peptide-based drug discovery.

It has been 80 years since Leonard Axel Jägerskiöld’s thorough marine faunistic inventory of the Swedish west coast (1921-1938), which represents the latest update of the Swedish sponge marine fauna. In this study, we present an update of the demosponge fauna with new specimens collected by the Swedish Taxonomic Initiative expeditions (2007-2008), new dredges (2012-2020), and SCUBA (2018–2020). Identifications were based on morphology and a molecular tree-based approach using the Folmer fragment of coxI, and the D3-D5 region of the 28S rRNA-encoding gene. From the 417 specimens examined, 57 different species were identified, of which five were identified to the genus/family level, eight were new reports for Sweden and one was new to science (Halisarca hansghanssoni sp. nov.). Furthermore, we reinstated the name Hymedesmia dujardinii (Bowerbank, 1866). The Swedish Taxonomic Initiative campaigns aimed to replicate the collecting efforts of the Jägerskiöld’s campaigns, thus making them easily comparable. Using the identified sponges of the Jägerskiöld’s inventory possibly changes in the Swedish sponge fauna over the last 80 years are discussed.