BMC Neurosci. 2024 Jul 6;25(1):32. doi: 10.1186/s12868-024-00880-1.

ABSTRACT

BACKGROUND: The postsynaptic density is an elaborate protein network beneath the postsynaptic membrane involved in the molecular processes underlying learning and memory. The postsynaptic density is built up from the same major proteins but its exact composition and organization differs between synapses. Mutations perturbing protein: protein interactions generally occurring in this network might lead to effects specific for cell types or processes, the understanding of which can be especially challenging.

RESULTS: In this work we use systems biology-based modeling of protein complex distributions in a simplified set of major postsynaptic proteins to investigate the effect of a hypomorphic Shank mutation perturbing a single well-defined interaction. We use data sets with widely variable abundances of the constituent proteins. Our results suggest that the effect of the mutation is heavily dependent on the overall availability of all the protein components of the whole network and no trivial correspondence between the expression level of the directly affected proteins and overall complex distribution can be observed.

CONCLUSIONS: Our results stress the importance of context-dependent interpretation of mutations. Even the weakening of a generally occurring protein: protein interaction might have well-defined effects, and these can not easily be predicted based only on the abundance of the proteins directly affected. Our results provide insight on how cell-specific effects can be exerted by a mutation perturbing a generally occurring interaction even when the wider interaction network is largely similar.

PMID:38971749 | DOI:10.1186/s12868-024-00880-1

BMC Plant Biol. 2024 Jul 6;24(1):641. doi: 10.1186/s12870-024-05366-0.

ABSTRACT

BACKGROUND: Early blight and brown leaf spot are often cited as the most problematic pathogens of tomato in many agricultural regions. Their causal agents are Alternaria spp., a genus of Ascomycota containing numerous necrotrophic pathogens. Breeding programs have yielded quantitatively resistant commercial cultivars, but fungicide application remains necessary to mitigate the yield losses. A major hindrance to resistance breeding is the complexity of the genetic determinants of resistance and susceptibility. In the absence of sufficiently resistant germplasm, we sequenced the transcriptomes of Heinz 1706 tomatoes treated with strongly virulent and weakly virulent isolates of Alternaria spp. 3 h post infection. We expanded existing functional gene annotations in tomato and using network statistics, we analyzed the transcriptional modules associated with defense and susceptibility.

RESULTS: The induced responses are very distinct. The weakly virulent isolate induced a defense response of calcium-signaling, hormone responses, and transcription factors. These defense-associated processes were found in a single transcriptional module alongside secondary metabolite biosynthesis genes, and other defense responses. Co-expression and gene regulatory networks independently predicted several D clade ethylene response factors to be early regulators of the defense transcriptional module, as well as other transcription factors both known and novel in pathogen defense, including several JA-associated genes. In contrast, the strongly virulent isolate elicited a much weaker response, and a separate transcriptional module bereft of hormone signaling.

CONCLUSIONS: Our findings have predicted major defense regulators and several targets for downstream functional analyses. Combined with our improved gene functional annotation, they suggest that defense is achieved through induction of Alternaria-specific immune pathways, and susceptibility is mediated by modulating hormone responses. The implication of multiple specific clade D ethylene response factors and upregulation of JA-associated genes suggests that host defense in this pathosystem involves ethylene response factors to modulate jasmonic acid signaling.

PMID:38971719 | DOI:10.1186/s12870-024-05366-0

Dev Cell. 2024 Jul 3:S1534-5807(24)00384-8. doi: 10.1016/j.devcel.2024.06.006. Online ahead of print.

ABSTRACT

Plant cell walls are essential for growth. The cell wall hemicellulose xyloglucan (XyG) is produced in the Golgi apparatus before secretion. Loss of the Arabidopsis galactosyltransferase MURUS3 (MUR3) decreases XyG d-galactose side chains and causes intracellular aggregations and dwarfism. It is unknown how changing XyG synthesis can broadly impact organelle organization and growth. We show that intracellular aggregations are not unique to mur3 and are found in multiple mutant lines with reduced XyG D-galactose side chains. mur3 aggregations disrupt subcellular trafficking and induce formation of intracellular cell-wall-like fragments. Addition of d-galacturonic acid onto XyG can restore growth and prevent mur3 aggregations. These results indicate that the presence, but not the composition, of XyG side chains is essential, likely by ensuring XyG solubility. Our results suggest that XyG polysaccharides are synthesized in a highly substituted form for efficient secretion and then later modified by cell-wall-localized enzymes to fine-tune cell wall properties.

PMID:38971156 | DOI:10.1016/j.devcel.2024.06.006

Cell. 2024 Jun 26:S0092-8674(24)00651-2. doi: 10.1016/j.cell.2024.06.011. Online ahead of print.

ABSTRACT

We identify a population of Protogenin-positive (PRTG+ve) MYChigh NESTINlow stem cells in the four-week-old human embryonic hindbrain that subsequently localizes to the ventricular zone of the rhombic lip (RLVZ). Oncogenic transformation of early Prtg+ve rhombic lip stem cells initiates group 3 medulloblastoma (Gr3-MB)-like tumors. PRTG+ve stem cells grow adjacent to a human-specific interposed vascular plexus in the RLVZ, a phenotype that is recapitulated in Gr3-MB but not in other types of medulloblastoma. Co-culture of Gr3-MB with endothelial cells promotes tumor stem cell growth, with the endothelial cells adopting an immature phenotype. Targeting the PRTGhigh compartment of Gr3-MB in vivo using either the diphtheria toxin system or chimeric antigen receptor T cells constitutes effective therapy. Human Gr3-MBs likely arise from early embryonic RLVZ PRTG+ve stem cells inhabiting a specific perivascular niche. Targeting the PRTGhigh compartment and/or the perivascular niche represents an approach to treat children with Gr3-MB.

PMID:38971152 | DOI:10.1016/j.cell.2024.06.011

Cell. 2024 Jul 3:S0092-8674(24)00653-6. doi: 10.1016/j.cell.2024.06.013. Online ahead of print.

ABSTRACT

Homologous recombination deficiency (HRD) is prevalent in cancer, sensitizing tumor cells to poly (ADP-ribose) polymerase (PARP) inhibition. However, the impact of HRD and related therapies on the tumor microenvironment (TME) remains elusive. Our study generates single-cell gene expression and T cell receptor profiles, along with validatory multimodal datasets from >100 high-grade serous ovarian cancer (HGSOC) samples, primarily from a phase II clinical trial (NCT04507841). Neoadjuvant monotherapy with the PARP inhibitor (PARPi) niraparib achieves impressive 62.5% and 73.6% response rates per RECIST v.1.1 and GCIG CA125, respectively. We identify effector regulatory T cells (eTregs) as key responders to HRD and neoadjuvant therapies, co-occurring with other tumor-reactive T cells, particularly terminally exhausted CD8+ T cells (Tex). TME-wide interferon signaling correlates with cancer cells upregulating MHC class II and co-inhibitory ligands, potentially driving Treg and Tex fates. Depleting eTregs in HRD mouse models, with or without PARP inhibition, significantly suppresses tumor growth without observable toxicities, underscoring the potential of eTreg-focused therapeutics for HGSOC and other HRD-related tumors.

PMID:38971151 | DOI:10.1016/j.cell.2024.06.013

Cell Rep Methods. 2024 Jul 1:100813. doi: 10.1016/j.crmeth.2024.100813. Online ahead of print.

ABSTRACT

Gene co-expression analysis of single-cell transcriptomes, aiming to define functional relationships between genes, is challenging due to excessive dropout values. Here, we developed a single-cell graphical Gaussian model (SingleCellGGM) algorithm to conduct single-cell gene co-expression network analysis. When applied to mouse single-cell datasets, SingleCellGGM constructed networks from which gene co-expression modules with highly significant functional enrichment were identified. We considered the modules as gene expression programs (GEPs). These GEPs enable direct cell-type annotation of individual cells without cell clustering, and they are enriched with genes required for the functions of the corresponding cells, sometimes at levels greater than 10-fold. The GEPs are conserved across datasets and enable universal cell-type label transfer across different studies. We also proposed a dimension-reduction method through averaging by GEPs for single-cell analysis, enhancing the interpretability of results. Thus, SingleCellGGM offers a unique GEP-based perspective to analyze single-cell transcriptomes and reveals biological insights shared by different single-cell datasets.

PMID:38971150 | DOI:10.1016/j.crmeth.2024.100813

Curr Opin Chem Biol. 2024 Jul 5;81:102493. doi: 10.1016/j.cbpa.2024.102493. Online ahead of print.

ABSTRACT

Growing environmental concerns and the urgency to address climate change have increased demand for the development of sustainable alternatives to fossil-derived fuels and chemicals. Microbial systems, possessing inherent biosynthetic capabilities, present a promising approach for achieving this goal. This review discusses the coupling of systems and synthetic biology to enable the elucidation and manipulation of microbial phenotypes for the production of chemicals that can substitute for petroleum-derived counterparts and contribute to advancing green biotechnology. The integration of artificial intelligence with metabolic engineering to facilitate precise and data-driven design of biosynthetic pathways is also discussed, along with the identification of current limitations and proposition of strategies for optimizing biosystems, thereby propelling the field of chemical biology towards sustainable chemical production.

PMID:38971129 | DOI:10.1016/j.cbpa.2024.102493

STAR Protoc. 2024 Jul 4;5(3):103173. doi: 10.1016/j.xpro.2024.103173. Online ahead of print.

ABSTRACT

Here, we present a protocol for analyzing the global metabolic landscape in breast tumors for the purpose of metabolism-based patient stratification. We describe steps for analyzing 1,454 metabolic genes representing 90 metabolic pathways and subjecting them to an algorithm that calculates the deregulation score of 90 pathways in each tumor sample, thus converting gene-level information into pathway-level information. We then detail procedures for performing clustering analysis to identify metabolic subtypes and using machine learning to develop a signature representing each subtype. For complete details on the use and execution of this protocol, please refer to Iqbal et al.1.

PMID:38970792 | DOI:10.1016/j.xpro.2024.103173

Bioinformatics. 2024 Jul 5:btae440. doi: 10.1093/bioinformatics/btae440. Online ahead of print.

ABSTRACT

SUMMARY: Computational cell-type deconvolution is an important analytic technique for modeling the compositional heterogeneity of bulk gene expression data. A conceptually new Bayesian approach to this problem, BayesPrism, has recently been proposed and has subsequently been shown to be superior in accuracy and robustness against model misspecifications by independent studies; however, given that BayesPrism relies on Gibbs sampling, it is orders of magnitude more computationally expensive than standard approaches. Here, we introduce the InstaPrism package which re-implements BayesPrism in a derandomized framework by replacing the time-consuming Gibbs sampling step with a fixed-point algorithm. We demonstrate that the new algorithm is effectively equivalent to BayesPrism while providing a considerable speed and memory advantage. Furthermore, the InstaPrism package is equipped with a precompiled, curated set of references tailored for a variety of cancer types, streamlining the deconvolution process.

AVAILABILITY AND IMPLEMENTATION: The package InstaPrism is freely available at: https://github.com/humengying0907/InstaPrism. The source code and evaluation pipeline used in this paper can be found at: https://github.com/humengying0907/InstaPrismSourceCode.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:38970377 | DOI:10.1093/bioinformatics/btae440

Syst Biol. 2024 Jul 5:syae034. doi: 10.1093/sysbio/syae034. Online ahead of print.

ABSTRACT

Dating phylogenetic trees to obtain branch lengths in time unit is essential for many downstream applications but has remained challenging. Dating requires inferring substitution rates that can change across the tree. While we can assume to have information about a small subset of nodes from the fossil record or sampling times (for fast-evolving organisms), inferring the ages of the other nodes essentially requires extrapolation and interpolation. Assuming a distribution of branch rates, we can formulate dating as a constrained maximum likelihood (ML) estimation problem. While ML dating methods exist, their accuracy degrades in the face of model misspecification where the assumed parametric statistical distribution of branch rates vastly differs from the true distribution. Notably, most existing methods assume rigid, often unimodal, branch rate distributions. A second challenge is that the likelihood function involves an integral over the continuous domain of the rates and often leads to difficult non-convex optimization problems. To tackle these two challenges, we propose a new method called Molecular Dating using Categorical-models (MD-Cat). MD-Cat uses a categorical model of rates inspired by non-parametric statistics and can approximate a large family of models by discretizing the rate distribution into k categories. Under this model, we can use the Expectation- Maximization (EM) algorithm to co-estimate rate categories and branch lengths in time units. Our model has fewer assumptions about the true distribution of branch rates than parametric models such as Gamma or LogNormal distribution. Our results on two simulated and real datasets of Angiosperms and HIV and a wide selection of rate distributions show that MD-Cat is often more accurate than the alternatives, especially on datasets with exponential or multimodal rate distributions.

PMID:38970346 | DOI:10.1093/sysbio/syae034

Nat Commun. 2024 Jul 5;15(1):5608. doi: 10.1038/s41467-024-49850-5.

ABSTRACT

Force transmission through adherens junctions (AJs) is crucial for multicellular organization, wound healing and tissue regeneration. Recent studies shed light on the molecular mechanisms of mechanotransduction at the AJs. However, the canonical model fails to explain force transmission when essential proteins of the mechanotransduction module are mutated or missing. Here, we demonstrate that, in absence of α-catenin, β-catenin can directly and functionally interact with vinculin in its open conformation, bearing physiological forces. Furthermore, we found that β-catenin can prevent vinculin autoinhibition in the presence of α-catenin by occupying vinculin´s head-tail interaction site, thus preserving force transmission capability. Taken together, our findings suggest a multi-step force transmission process at AJs, where α-catenin and β-catenin can alternatively and cooperatively interact with vinculin. This can explain the graded responses needed to maintain tissue mechanical homeostasis and, importantly, unveils a force-bearing mechanism involving β-catenin and extended vinculin that can potentially explain the underlying process enabling collective invasion of metastatic cells lacking α-catenin.

PMID:38969637 | DOI:10.1038/s41467-024-49850-5

Plant J. 2024 Jul 5. doi: 10.1111/tpj.16917. Online ahead of print.

ABSTRACT

HSP90Cs are essential molecular chaperones localized in the plastid stroma that maintain protein homeostasis and assist the import and thylakoid transport of chloroplast proteins. While HSP90C contains all conserved domains as an HSP90 family protein, it also possesses a unique feature in its variable C-terminal extension (CTE) region. This study elucidated the specific function of this HSP90C CTE region. Our phylogenetic analyses revealed that this intrinsically disordered region contains a highly conserved DPW motif in the green lineages. With biochemical assays, we showed that the CTE is required for the chaperone to effectively interact with client proteins PsbO1 and LHCB2 to regulate ATP-independent chaperone activity and to effectuate its ATP hydrolysis. The CTE truncation mutants could support plant growth and development reminiscing the wild type under normal conditions except for a minor phenotype in cotyledon when expressed at a level comparable to wild type. However, higher HSP90C expression was observed to correlate with a stronger response to specific photosystem II inhibitor DCMU, and CTE truncations dampened the response. Additionally, when treated with lincomycin to inhibit chloroplast protein translation, CTE truncation mutants showed a delayed response to PsbO1 expression repression, suggesting its role in chloroplast retrograde signaling. Our study therefore provides insights into the mechanism of HSP90C in client protein binding and the regulation of green chloroplast maturation and function, especially under stress conditions.

PMID:38969341 | DOI:10.1111/tpj.16917

Biosystems. 2024 Jul 3:105262. doi: 10.1016/j.biosystems.2024.105262. Online ahead of print.

ABSTRACT

We attempt in this article to formulate a conceptual and testable framework weaving Cosmos, Mind and Matter into a whole. We build on three recent discoveries, each requiring more evidence: i. The particles of the Standard Model, SU(3) x SU(2) x U(1), are formally capable of collective autocatalysis. This leads us to ask what roles such autocatalysis may have played in Cosmogenesis, and in trying to answer, Why our Laws? Why our Constants? A capacity of the particles of SU(3) x SU(2) x U(1) for collective autocatalysis may be open to experimental test, stunning if confirmed. ii. Reasonable evidence now suggests that matter can expand spacetime. The first issue is to establish this claim at or beyond 5 sigma if that can be done. If true, this process may elucidate Dark Matter, Dark Energy and Inflation and require alteration of Einstein's Field Equations. Cosmology would be transformed. iii. Evidence at 6.49 Sigma suggests that mind can alter the outcome of the two-slit experiment. If widely and independently verified, the foundations of quantum mechanics must be altered. Mind plays a role in the universe. That role may include Cosmic Mind. OUR CONSIDERATIONS CONCERN: 1. Ontologically Real Potentia and the Unmanifest; 2. Nonlocality as Fundamental; 3. Res potentia, Res extensa, and Actualization; 4. Mind and Qualia, Mind is not in Spacetime; 5. Quantum Vacuum = Potentia not in Spacetime = Mind not in Spacetime; 6. Mind can Actualize Potentia; 7. The emergence of the classical world; 8. Co-evolution of evermore complex matter; 9. Why "My Mind"?; 10. Each embodied mind is coupled bilaterally to the Quantum Vacuum that is Cosmic Mind; 11. Responsible Free Will.

PMID:38969235 | DOI:10.1016/j.biosystems.2024.105262

Redox Biol. 2024 Jun 26;75:103254. doi: 10.1016/j.redox.2024.103254. Online ahead of print.

ABSTRACT

Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα) signaling in the brain plays a critical role in regulating neuronal Ca2+ homeostasis. Its dysfunctional activity is associated with various neurological and neurodegenerative disorders, including Parkinson's disease (PD). Using computational modeling analysis, we predicted that, two essential cysteine residues contained in CaMKIIα, Cys30 and Cys289, may undergo redox modifications impacting the proper functioning of the CaMKIIα docking site for Ca2+/CaM, thus impeding the formation of the CaMKIIα:Ca2+/CaM complex, essential for a proper modulation of CaMKIIα kinase activity. Our subsequent in vitro investigations confirmed the computational predictions, specifically implicating Cys30 and Cys289 residues in impairing CaMKIIα:Ca2+/CaM interaction. We observed CaMKIIα:Ca2+/CaM complex disruption in dopamine (DA) nigrostriatal neurons of post-mortem Parkinson's disease (PD) patients' specimens, addressing the high relevance of this event in the disease. CaMKIIα:Ca2+/CaM complex disruption was also observed in both in vitro and in vivo rotenone models of PD, where this phenomenon was associated with CaMKIIα kinase hyperactivity. Moreover, we observed that, NADPH oxidase 2 (NOX2), a major enzymatic generator of superoxide anion (O2●-) and hydrogen peroxide (H2O2) in the brain with implications in PD pathogenesis, is responsible for CaMKIIα:Ca2+/CaM complex disruption associated to a stable Ca2+CAM-independent CaMKIIα kinase activity and intracellular Ca2+ accumulation. The present study highlights the importance of oxidative stress, in disturbing the delicate balance of CaMKIIα signaling in calcium dysregulation, offering novel insights into PD pathogenesis.

PMID:38968922 | DOI:10.1016/j.redox.2024.103254

J Environ Manage. 2024 Jul 4;365:121662. doi: 10.1016/j.jenvman.2024.121662. Online ahead of print.

ABSTRACT

Fire-induced changes in vegetation composition due to fire-regime intensification are leading to alterations in ecosystem services that might threaten their future sustainability. Fire recurrence, in particular, could be a key driver shaping ecosystem service resilience in fire-prone ecosystems. This study evaluates the impact of fire recurrence, over twenty-four years, on the potential supply capacity of ten regulating, provisioning, and cultural services selected as critical services by stakeholders and experts. We assessed fire effects in four fire-prone landscapes dominated by species with different functional-traits response to fire (i.e., obligate seeder vs resprouter species). Trends in the potential supply capacity linked to fire recurrence were estimated by applying a supervised classification of Land Use and Land Cover (LULC) classes performed using Landsat imagery, associated to an ecosystem service capacity matrix adapted to the local socio-ecological context. In landscapes dominated by seeders, fire recurrence broke off the potential supply capacity of services traditionally associated to mature forest cover (i.e., the predicted probability of a decrease in the potential supply capacity of climate regulation, timber, wood fuel, mushroom production, tourism, landscape aesthetic, and cultural heritage occurred with high fire recurrence). In landscapes dominated by resprouter species, the effect of fire recurrence was partially buffered in the short-term after fire and no substantial differences in trends of change were found (i.e., equal predicted probability in the potential supply capacity of ecosystem services regardless of fire recurrence). We detected two new opportunities for ecosystems service supply associated to fire recurrence: livestock and honey production, especially in sites dominated by seeders. These findings provide valuable information aiming at recovering post-fire ecosystem service potential supply to partially counterbalance the loss in the socio-ecological system. When the main post-fire restoration goal is preserving ecosystem service resilience in fire-prone ecosystems, establishing management strategies focused on promoting resprouter species could aid mitigating the fire-driven loss of their supply capacity.

PMID:38968878 | DOI:10.1016/j.jenvman.2024.121662

Mar Environ Res. 2024 Jun 29;199:106627. doi: 10.1016/j.marenvres.2024.106627. Online ahead of print.

ABSTRACT

DNA metabarcoding and stable isotope analysis have significantly advanced our understanding of marine trophic ecology, aiding systematic research on foraging habits and species conservation. In this study, we employed these methods to analyse faecal and blood samples, respectively, to compare the trophic ecology of two Red-billed Tropicbird (Phaethonaethereus; Linnaeus, 1758) colonies on Mexican islands in the Pacific. Trophic patterns among different breeding stages were also examined at both colonies. Dietary analysis reveals a preference for epipelagic fish, cephalopods, and small crustaceans, with variations between colonies and breeding stages. Isotopic values (δ15N and δ13C) align with DNA metabarcoding results, with wider niches during incubation stages. Differences in diet are linked to environmental conditions and trophic plasticity among breeding stages, influenced by changing physiological requirements and prey availability. Variations in dietary profiles reflect contrasting environmental conditions affecting local prey availability.

PMID:38968803 | DOI:10.1016/j.marenvres.2024.106627

Stem Cell Res. 2024 Jul 2;79:103486. doi: 10.1016/j.scr.2024.103486. Online ahead of print.

ABSTRACT

Pluripotent stem cells were generated through the electroporation of episomal plasmids, containing crucial reprogramming factors, into skin fibroblasts extracted from a female Alzheimer's patient harboring the PSEN1 709 T > C (p.Phe237Leu) heterozygous mutation. The pluripotent stem cells exhibit a normal karyotype and express pivotal stem cell markers including TRA-1-60, Nanog, SOX2, and OCT4. Furthermore, their capacity to differentiate into the three germ layers in in vivo teratoma experiments has been substantiated. The pluripotent stem cell line can serve as a cellular model for Alzheimer's disease, offering significant value in elucidating the pathogenesis and therapeutic strategies of the disease.

PMID:38968760 | DOI:10.1016/j.scr.2024.103486

Proc Natl Acad Sci U S A. 2024 Jul 9;121(28):e2322066121. doi: 10.1073/pnas.2322066121. Epub 2024 Jul 5.

ABSTRACT

The Wnt/Wingless signaling pathway plays critical roles in metazoan development and energy metabolism, but its role in regulating lipid homeostasis remains not fully understood. Here, we report that the activation of canonical Wnt/Wg signaling promotes lipolysis while concurrently inhibiting lipogenesis and fatty acid β-oxidation in both larval and adult adipocytes, as well as cultured S2R+ cells, in Drosophila. Using RNA-sequencing and CUT&RUN (Cleavage Under Targets & Release Using Nuclease) assays, we identified a set of Wnt target genes responsible for intracellular lipid homeostasis. Notably, active Wnt signaling directly represses the transcription of these genes, resulting in decreased de novo lipogenesis and fatty acid β-oxidation, but increased lipolysis. These changes lead to elevated free fatty acids and reduced triglyceride (TG) accumulation in adipocytes with active Wnt signaling. Conversely, downregulation of Wnt signaling in the fat body promotes TG accumulation in both larval and adult adipocytes. The attenuation of Wnt signaling also increases the expression of specific lipid metabolism-related genes in larval adipocytes, wing discs, and adult intestines. Taken together, these findings suggest that Wnt signaling-induced transcriptional repression plays an important role in regulating lipid homeostasis by enhancing lipolysis while simultaneously suppressing lipogenesis and fatty acid β-oxidation.

PMID:38968125 | DOI:10.1073/pnas.2322066121

Proc Natl Acad Sci U S A. 2024 Jul 9;121(28):e2322203121. doi: 10.1073/pnas.2322203121. Epub 2024 Jul 5.

ABSTRACT

Targeting cell surface molecules using radioligand and antibody-based therapies has yielded considerable success across cancers. However, it remains unclear how the expression of putative lineage markers, particularly cell surface molecules, varies in the process of lineage plasticity, wherein tumor cells alter their identity and acquire new oncogenic properties. A notable example of lineage plasticity is the transformation of prostate adenocarcinoma (PRAD) to neuroendocrine prostate cancer (NEPC)-a growing resistance mechanism that results in the loss of responsiveness to androgen blockade and portends dismal patient survival. To understand how lineage markers vary across the evolution of lineage plasticity in prostate cancer, we applied single-cell analyses to 21 human prostate tumor biopsies and two genetically engineered mouse models, together with tissue microarray analysis on 131 tumor samples. Not only did we observe a higher degree of phenotypic heterogeneity in castrate-resistant PRAD and NEPC than previously anticipated but also found that the expression of molecules targeted therapeutically, namely PSMA, STEAP1, STEAP2, TROP2, CEACAM5, and DLL3, varied within a subset of gene-regulatory networks (GRNs). We also noted that NEPC and small cell lung cancer subtypes shared a set of GRNs, indicative of conserved biologic pathways that may be exploited therapeutically across tumor types. While this extreme level of transcriptional heterogeneity, particularly in cell surface marker expression, may mitigate the durability of clinical responses to current and future antigen-directed therapies, its delineation may yield signatures for patient selection in clinical trials, potentially across distinct cancer types.

PMID:38968122 | DOI:10.1073/pnas.2322203121

STAR Protoc. 2024 Jul 4;5(3):103164. doi: 10.1016/j.xpro.2024.103164. Online ahead of print.

ABSTRACT

Optogenetic manipulation has proven a powerful tool for investigating the mechanisms underlying the function of neuronal networks, but implementing the technique on mammals during early development remains challenging. Here, we present a comprehensive workflow to specifically manipulate mitral/tufted cells (M/TCs), the output neurons in the olfactory circuit, mediated by adeno-associated virus (AAV) transduction and light stimulation in neonatal mice and monitor neuronal and network activity with in vivo electrophysiology. This method represents an efficient approach to elucidate functional brain development. For complete details on the use and execution of this protocol, please refer to Chen et al.1,2,3.

PMID:38968078 | DOI:10.1016/j.xpro.2024.103164