Biology subjects

Patel, A. J.

Publications and source records attributed to Patel, A. J..

17 recordsLinked to original sources

bioRxiv2025

PRC2 Restricts Malignant Peripheral Nerve Sheath Tumorigenesis in a Genetically Engineered Mouse Model of MPNST

Polycomb Repressive Complex 2 (PRC2), which normally regulates transcriptional silencing, chromatin compaction, and stem cell biology, has both oncogenic and tumor suppressor roles in cancer development depending on tumor type. Malignant peripheral nerve sheath tumor (MPNST), characterized by NF1, CDKN2A and PRC2 loss, is an aggressive subtype of sarcoma with poor prognosis and no effective therapy. In high-grade human MPNSTs, inactivating mutations in PRC2 core components SUZ12 or EED are prevalent and contributes to oncogenic transformation and progression of MPNST. How PRC2 inactivation contributes to MPNST pathogenesis, however, remains incompletely understood. Here we show that genetic inactivation of Eed in addition to Nf1 and Cdkn2a in the Schwann-progenitor lineage leads to widespread tumorigenesis within the sciatic nerve compartment of mice. In contrast, loss of Nf1 and Cdkn2a is insufficient to drive tumorigenesis in the sciatic nerve but leads to MPNST development in other anatomic locations with a longer latency. Single-nucleus multiome sequencing of the sciatic nerves revealed that PRC2-loss reprograms Nf1/Cdkn2a-deficient Schwann-lineage cells toward a dedifferentiated, neural crest stem cell-like state that resembles the transcriptomic signatures of human PRC2-loss MPNST. Together, these findings suggest a context-dependent tumor suppressive role for PRC2 within the sciatic nerve and establish a novel mouse model that recapitulates human PRC2-loss MPNST. SIGNIFICANCEWe present a novel genetically engineered mouse model that faithfully recapitulates human PRC2-loss MPNST, enabling mechanistic and preclinical studies of malignant transformation in the context of PRC2 loss.

cancer biology↗

bioRxiv2024

Cell type transcriptional identities are maintained in cultured ex vivo human brain tissue

It is becoming more broadly accepted that human-based models are needed to better understand the complexities of the human nervous system and its diseases. The recently developed human brain organotypic culture model is one highly promising model that requires the involvement of neurosurgeons and neurosurgical patients. Studies have investigated the electrophysiological properties of neurons in such ex vivo human tissues, but the maintenance of other cell types within explanted brain remains largely unknown. Here, using single-nucleus RNA sequencing, we systematically evaluate the transcriptional identities of the various cell types found in six patient samples after fourteen days in culture (83,501 nuclei from day 0 samples and 45,738 nuclei from day 14 samples). We used two pediatric temporal lobectomy samples, an adult frontal cortex sample, two IDH wild-type glioblastoma samples, and one medulloblastoma sample. We found remarkably high correlations of day 14 transcriptional identities to day 0 tissue, especially in tumor cells (r = 0.90 to 0.93), though microglia (r = 0.86), oligodendrocytes (r = 0.80), pericytes (r = 0.77), endothelial cells (r = 0.78), and fibroblasts (r = 0.76) showed strong preservation of their transcriptional profiles as well. Astrocytes and excitatory neurons showed more moderate preservation (r = 0.66 and 0.47, respectively). Because the main difficulty with organotypic brain cultures is the acquisition of human tissue, which is readily available to neurosurgeons, this model is easily accessible to neurosurgeon-scientists and neurosurgeons affiliated with research laboratories. Broad uptake of this more representative model should prompt advances in our understanding of many uniquely human diseases, lead to more reliable clinical trial performance, and ultimately yield better therapies for our patients.

neuroscience↗

bioRxiv2024

Delivery of Peptide Coacervates to Form Stable Interaction Hubs In Cells

Cells contain membrane-bound and membraneless organelles that operate as spatially distinct biochemical niches. However, these reaction centers lose fidelity due to aging or disease. A grand challenge for biomedicine is restoring or augmenting cellular functionalities. Although commonly tackled by gene replacement therapy, an exciting new strategy is the delivery of protein-based materials that directly interact with and alter intracellular pathways. In this study, we sought to develop long-lasting materials capable of cellular uptake, akin to artificial organelles or synthetic interaction hubs. We show efficient delivery of micron-size peptide-based compartments into a variety of cell types. By loading coacervates with nanobodies and bioPROTACs, we demonstrate successful native target sequestration, and hub bioreactor function to selectively degrade targets inside human cells. These results represent an important step toward the development of synthetic organelles that can be fabricated in vitro and taken up by cells for applications in cell engineering and regenerative medicine.

synthetic biology↗

bioRxiv2024

Laminin β4 is required for the development of human peripheral sensory neurons

The extracellular matrix (ECM) is a mixture of glycoproteins and fibrous proteins that provide the biophysical properties necessary to maintain cellular homeostasis. ECM integrity is of particular importance during development, where it allows proper migration and cellular differentiation. Laminins are ECM heterotrimeric proteins consisting of , {beta}, and {gamma} chains. There are five known chains, four {beta} chains, and three {gamma} chains. Thus, there are 60 potential combinations for laminin trimers, however only 16 laminin trimers have been identified to date. Furthermore, none of them contain laminin {beta}4 and its function is unknown. Here, we sought to characterize the role of LAMB4 (the gene encoding laminin {beta}4) during human embryonic development of the peripheral sensory nervous system. Using human pluripotent stem cells (hPSCs), we found that LAMB4 is expressed in the ectoderm in the early stages of sensory neuron (SN) specification. SNs, part of the peripheral nervous system, are specialized neurons that detect pain, temperature, and touch. Surprisingly, more than 20 million people in the US have some form of peripheral nerve damage (including SNs), however there are very few treatment options available. Learning about the biology of peripheral neurons will uncover potential new therapeutic targets, thus we focused on understanding the effects of LAMB4 in SNs. First, we knocked out LAMB4 in hPSCs, using CRISPR/Cas9, and found that loss of LAMB4 impairs the migration of the SN progenitors neural crest cells (NCCs) and harms SN development and survival. To assess if LAMB4 has clinical relevance, we studied the genetic disorder Familial Dysautonomia (FD), which specifically affects the peripheral nervous system. FD is caused by a mutation in ELP1 (a component of the Elongator complex) leading to developmental and degenerative defects in SNs. A previous report showed that patients with severe FD harbor additional single nucleotide variants in LAMB4. We found that these variants sharply downregulate the expression of LAMB4 and laminin {beta}4 levels in SNs differentiated from induced pluripotent stem cells (iPSCs) reprogramed from patients with severe FD. Moreover, a healthy ECM is sufficient to rescue the developmental phenotypes of FD, further confirming that ECM defects contribute significantly to the etiology of FD. Finally, we found that LAMB4/laminin {beta}4 is necessary for actin filament accumulation and it interacts with laminin 4 and laminin {gamma}3, forming the laminin-443, a previously unreported laminin trimer. Together, these results show that LAMB4 is a critical, but largely unknown gene required for SN development and survival.

cell biology↗

bioRxiv2024

Leveraging Single-Cell Sequencing to Classify and Characterize Tumor Subgroups in Bulk RNA-Sequencing Data

Accurate classification of cancer subgroups is essential for precision medicine, tailoring treatments to individual patients based on their cancer subtypes. In recent years, advances in high-throughput sequencing technologies have enabled the generation of large-scale transcriptomic data from cancer samples. These data have provided opportunities for developing computational methods that can improve cancer subtyping and enable better personalized treatment strategies. Here in this study, we evaluated different feature selection schemes in the context of meningioma classification. While the scheme relying solely on bulk transcriptomic data showed good classification accuracy, it exhibited confusion between malignant and benign molecular classes in approximately ~8% of meningioma samples. In contrast, models trained on features learned from meningioma single-cell data accurately resolved the sub-groups confused by bulk-transcriptomic data but showed limited overall accuracy. To integrate interpretable features from the bulk (n=78 samples) and single-cell profiling (~10K cells), we developed an algorithm named CLIPPR which combines the top-performing single-cell models with RNA-inferred copy number variation (CNV) signals and the initial bulk model to create a meta-model, which exhibited the strongest performance in meningioma classification. CLIPPR showed superior overall accuracy and resolved benign-malignant confusion as validated on n=792 bulk meningioma samples gathered from multiple institutions. Finally, we showed the generalizability of our algorithm using our in-house single-cell (~200K cells) and bulk TCGA glioma data (n=711 samples). Overall, our algorithm CLIPPR synergizes the resolution of single-cell data with the depth of bulk sequencing and enables improved cancer sub-group diagnoses and insights into their biology.

bioinformatics↗

bioRxiv2024

Meningioma transcriptomic landscape demonstrates novel subtypes with regional associated biology and patient outcome.

Meningiomas, the most common intracranial tumor, though mostly benign can be recurrent and fatal. WHO grading does not always identify high risk meningioma and better characterizations of their aggressive biology is needed. To approach this problem, we combined 13 bulk RNA-Seq datasets to create a dimension-reduced reference landscape of 1298 meningiomas. Clinical and genomic metadata effectively correlated with landscape regions which led to the identification of meningioma subtypes with specific biological signatures. Time to recurrence also correlated with the map location. Further, we developed an algorithm that maps new patients onto this landscape where nearest neighbors predict outcome. This study highlights the utility of combining bulk transcriptomic datasets to visualize the complexity of tumor populations. Further, we provide an interactive tool for understanding the disease and predicting patient outcome. This resource is accessible via the online tool Oncoscape, where the scientific community can explore the meningioma landscape.

cancer biology↗

bioRxiv2023

NF2 Loss-of-Function and Hypoxia Drive Radiation Resistance in Grade 2 Meningiomas

BackgroundWorld Health Organization Grade 2 meningiomas (G2Ms) exhibit an aggressive natural history characterized by recurrence and therapy resistance. G2Ms with histopathological necrosis have been associated with worse local control (LC) following radiation therapy, but drivers and biomarkers of radiation resistance in these G2Ms remain unknown. MethodsWe performed genetic sequencing and histopathological analysis of 113 G2Ms and investigated the role of intratumoral hypoxia as well as genes of interest through knockdown and clonogenic survival following ionizing radiation. Lastly, we performed transcriptional profiling of our in vitro model and 18 G2M tumors using RNA sequencing. ResultsNF2 loss-of-function (LOF) mutations were associated with necrosis in G2Ms (p=0.0127). Tumors with NF2 mutation and necrosis had worse post-radiation LC compared to NF2 wildtype tumors without necrosis (p=0.035). Under hypoxic conditions, NF2 knockdown increased radiation resistance in vitro (p<0.001). Bulk RNA sequencing of our in vitro model revealed NF2- and hypoxia-specific changes and a 50-gene set signature specific to radiation resistant, NF2 knockdown and hypoxic cells, which could distinguish NF2 mutant and necrotic patient G2Ms by unsupervised clustering. Gene set enrichment analysis of patient tumor and in vitro data revealed downregulation of apoptosis and upregulation of proliferation in NF2-deficient and hypoxic cells, which we validated with functional assays. ConclusionsNF2 LOF in the setting of hypoxia confers radiation resistance through transcriptional programs that reduce apoptosis and promote proliferation. These pathways may identify tumors resistant to radiation and represent therapeutic targets that in the future could improve LC in patients with radiation resistant G2Ms. KEY POINTS1. Spontaneous necrosis with NF2 mutations is associated with radio-resistance in WHO G2Ms. 2. NF2 knockdown in the setting of hypoxia confers radio-resistance to meningioma cells in vitro and is driven by increased cell proliferation and decreased apoptosis. IMPORTANCE OF THE STUDYWorld Health Organization Grade 2 meningiomas (G2M) are often treated with surgical resection followed by radiation, especially in the case of recurrence. However, the mechanisms underlying radiation resistance in G2Ms remain to be identified, and moreover, we lack biomarkers to distinguish G2Ms that will respond to radiotherapy from those that are refractory. In this study we perform histological and molecular analysis of a large cohort of G2Ms to identify predictors of radiation resistance. Using these data and an in vitro model of radiation therapy, we demonstrate that radiation resistance in G2Ms is likely driven by the combination of NF2 gene mutations and the hypoxia that accompanies tumor necrosis. Patients whose tumors bear these two features may therefore benefit from alternative treatments that target specific pathways implicated in radiation resistance.

molecular biology↗

bioRxiv2023

Genipin Crosslinks the Extracellular Matrix to Rescue Developmental and Degenerative Defects, and Accelerates Regeneration of Peripheral Neurons

The peripheral nervous system (PNS) is essential for proper body function. A high percentage of the population suffer nerve degeneration or peripheral damage. For example, over 40% of patients with diabetes or undergoing chemotherapy develop peripheral neuropathies. Despite this, there are major gaps in the knowledge of human PNS development and therefore, there are no available treatments. Familial Dysautonomia (FD) is a devastating disorder that specifically affects the PNS making it an ideal model to study PNS dysfunction. FD is caused by a homozygous point mutation in ELP1 leading to developmental and degenerative defects in the sensory and autonomic lineages. We previously employed human pluripotent stem cells (hPSCs) to show that peripheral sensory neurons (SNs) are not generated efficiently and degenerate over time in FD. Here, we conducted a chemical screen to identify compounds able to rescue this SN differentiation inefficiency. We identified that genipin, a compound prescribed in Traditional Chinese Medicine for neurodegenerative disorders, restores neural crest and SN development in FD, both in the hPSC model and in a FD mouse model. Additionally, genipin prevented FD neuronal degeneration, suggesting that it could be offered to patients suffering from PNS neurodegenerative disorders. We found that genipin crosslinks the extracellular matrix, increases the stiffness of the ECM, reorganizes the actin cytoskeleton, and promotes transcription of YAP-dependent genes. Finally, we show that genipin enhances axon regeneration in an in vitro axotomy model in healthy sensory and sympathetic neurons (part of the PNS) and in prefrontal cortical neurons (part of the central nervous system, CNS). Our results suggest genipin can be used as a promising drug candidate for treatment of neurodevelopmental and neurodegenerative diseases, and as a enhancer of neuronal regeneration. One sentence summaryGenipin rescues the developmental and degenerative phenotypes of the peripheral neuropathy familial dysautonomia and enhances neuron regeneration after injury.

neuroscience↗

bioRxiv2022

Single-cell multi-omic analysis of the vestibular schwannoma ecosystem uncovers a nerve injury-like state

Vestibular schwannomas (VS) are benign tumors that lead to significant neurologic and otologic morbidity. How VS heterogeneity and the tumor microenvironment (TME) contribute to the pathogenesis of these tumors remains poorly understood. We performed scRNA-seq on 15 VS samples, with paired scATAC-seq in six samples. We identified diverse Schwann cell (SC), stromal, and immune populations in the VS TME and found that repair-like and MHC-II antigen presenting subtype SCs are associated with increased myeloid cell infiltrate, implicating a nerve injury-like process. Deconvolution analysis of RNA-expression data from 175 tumors revealed Injury-like tumors are associated with larger tumor size, and scATAC-seq identified transcription factors associated with nerve repair among SCs from Injury-like tumors. Ligand-receptor analysis and functional in vitro experiments suggested that SCs recruit monocytes. Our study indicates that Injury-like SCs may cause tumor growth via myeloid cell recruitment and identifies molecular pathways that may be targeted to prevent tumor progression.

cancer biology↗

bioRxiv2022

PRC2 Inactivating Mutations in Cancer are Synthetic Lethal with DNMT1 Targeted Therapy via Enhanced Viral Mimicry

Polycomb Repressive Complex 2 (PRC2) establishes and maintains di- and tri-methylation at histone 3 at lysine 27 (H3K27me2/3) in the genome and plays oncogenic and tumor suppressor roles in context-dependent cancer pathogenesis. While there is clinical success of therapeutically targeting PRC2 core component, EZH2, in PRC2-dependent cancers (e.g., follicular lymphoma, epithelioid sarcoma), it remains an unmet therapeutic bottleneck in PRC2-inactivated cancer. Biallelic inactivating mutations in PRC2 core components are a hallmark feature of high-grade malignant peripheral nerve sheath tumor (MPNST), an aggressive subtype of sarcoma with poor prognosis and no effective targeted therapeutics. Using a custom RNAi-based drop out screen, we observed that PRC2-inactivation is synthetic lethal with DNA methyltransferase 1 (DNMT1) downregulation; we further observed that small molecule DNMT inhibitors (DNMTis) resulted in enhanced cytotoxicity and antitumor response in PRC2-loss cancer context in vitro and in vivo. Mechanistically, DNMTi-mediated de-repression of retrotransposons (e.g., endogenous retroviral elements (ERVs)/LTR, LINE, SINE) and gene targets is partly restricted by PRC2, which potentially contributes to limited therapeutic activity in PRC2-wild-type (wt) cancer context. In contrast, DNMTi treatment synergizes with PRC2 inactivation and cooperatively amplifies the expression of retrotransposons (e.g., ERV/LTR, LINE, SINE), and subsequent viral mimicry response that promotes robust cell death in part through PKR-dependent double stranded-RNA (dsRNA) sensing. Collectively, our observations posit DNA methylation as a safeguard against anti-tumorigenic cell fate decisions in the context of PRC2-inactivation to promote cancer pathogenesis. Further, they identified a novel targeted therapeutic strategy in PRC2-inactivated MPNST and delineated the PRC2-inactivated cancer context for future preclinical exploration and clinical investigation of DNMT1-targeted therapies in cancer. SIGNIFICANCEPRC2-inactivation drives oncogenesis in various cancers but therapeutically targeting PRC2-loss has remained challenging. Here we show that PRC2 inactivating mutations sets up a tumor context-specific liability for synthetic lethal interaction with genetic and therapeutic inhibition of DNMT1. DNMT1 inhibitor-induced cytotoxicity in PRC2-loss cancer context is accompanied by innate immune signaling signature through PKR-mediated sensing of endogenous retrotransposons. These observations posit a therapeutic window via direct anti-tumor effect by DNMT1 inhibitors in PRC2-loss cancers, and point to potentials to be combined with innovative immunotherapeutic strategies to capitalize on innate immune signaling activation.

cancer biology↗

bioRxiv2022

Tumor-intrinsic PRC2 inactivation drives a context-dependent immune-desert tumor microenvironment and confers resistance to immunotherapy

Immune checkpoint blockade (ICB) has demonstrated clinical success in "inflamed" tumors with significant T-cell infiltrates, but tumors with an immune-desert tumor microenvironment (TME) fail to benefit. The tumor cell-intrinsic molecular mechanisms of the immune-desert phenotype remain poorly understood. Here, we demonstrate that inactivation of the Polycomb-repressive complex 2 (PRC2) core components, EED or SUZ12, a prevalent genetic event in malignant peripheral nerve sheath tumor (MPNST) and sporadically in other cancer types, drives a context-dependent immune-desert TME. PRC2 inactivation reprograms the chromatin landscape that leads to a cell-autonomous shift from primed baseline signaling-dependent cellular responses (e.g., interferon {gamma}) to PRC2-regulated development and cellular differentiation transcriptional programs. Further, PRC2 inactivation reprograms the TME, leads to diminished tumor immune infiltrates and immune evasion through reduced chemokine production and impaired antigen presentation and T-cell priming, and confers ICB primary resistance through blunted T-cell recruitment in vivo. We demonstrate that strategies that enhancing innate immunity via intratumoral delivery of inactivated modified vaccinia virus Ankara (MVA) leads to increased tumor immune infiltrates and sensitizes PRC2-loss tumors to ICB. Our results provide novel molecular mechanisms of context-dependent dysfunctional epigenetic reprogramming that underline the immune-desert phenotype in MPNST and other cancers with PRC2 inactivation. Importantly, our findings highlight genetic-inactivation of PRC2 as a novel context-dependent ICB therapeutic resistance biomarker in cancer, and caution that therapeutic strategies that non-selectively target PRC2 in the host may lead to undesirable context-dependent immune evasion and ICB resistance in tumors. Our studies also point to intratumoral delivery of immunogenic therapeutic viruses as an initial strategy to modulate the immune-desert TME and capitalize on the clinical benefit of ICB.

cancer biology↗

bioRxiv2021

OSBP-mediated cholesterol transfer determines epithelial polarity and associated cargo secretion

Golgi lipid environment regulates sorting and cargo secretion. However, the mechanisms that spatiotemporally control the lipid composition of the secretory membranes to drive cargo trafficking are poorly understood. Lipid transfer proteins regulate the concentration of specific lipids at membrane contact sites. We hypothesised that by catalysing cholesterol/PI(4)P exchange at ER-trans-Golgi membrane contact sites the lipid transfer protein oxysterol binding protein (OSBP) affects the secretion of a subset of cargoes. Here, we report that OSBP is a major epithelial protein as its inhibition leads to complete loss of apico-basal polarity. By mapping the OSBP proximity proteome with the biotin ligase TurboID, we found that OSBP controls the secretion of multiple membrane associated proteins, including key polarity determinants such as E-cadherin. Mechanistically, we established that OSBP contributes to E-cadherin secretion by supplying cholesterol to post-Golgi membranes. Importantly, when cells downregulate cell-cell junctions upon epithelial-to-mesenchymal transition, they re-wire their lipid homeostasis and downregulate OSBP as well, thus altering the trafficking of the OSBP-dependent secretory cargoes.

cell biology↗

bioRxiv2021

XCVATR: Detection and Characterization of Variant Impact on the Embeddings of Single -Cell and Bulk RNA-Sequencing Samples

Gene expression profiling via RNA-sequencing has become standard for measuring and analyzing the gene activity in bulk and at single cell level. Increasing sample sizes and cell counts provides substantial information about transcriptional architecture of samples. In addition to quantification of expression at cellular level, RNA-seq can be used for detecting of variants, including single nucleotide variants and small insertions/deletions and also large variants such as copy number variants. The joint analysis of variants with transcriptional state of cells or samples can provide insight about impact of mutations. To provide a comprehensive method to jointly analyze the genetic variants and cellular states, we introduce XCVATR, a method that can identify variants, detect local enrichment of expressed variants, within embedding of samples and cells. The embeddings provide information about cellular states among cells by defining a cell-cell distance metric. Unlike clustering algorithms, which depend on a cell-cell distance and use it to define clusters that explain cell clusters globally, XCVATR detects the local enrichment of expressed variants in the embedding space such that embedding can be computed using any type of measurement or method, for example by PCA or tSNE of the expression levels. XCVATR searches local patterns of association of each variant with the positions of cells in an embedding of the cells. XCVATR also visualizes the local clumps of small and large-scale variant calls in single cell and bulk RNA-sequencing datasets. We perform simulations and demonstrate that XCVATR can identify the enrichments of expressed variants. We also apply XCVATR on single cell and bulk RNA-seq datasets and demonstrate its utility.

bioinformatics↗

bioRxiv2021

scRegulocity: Detection of local RNA velocity patterns in embeddings of single cell RNA-Seq data

Single cell RNA-sequencing has revolutionized transcriptome analysis. ScRNA-seq provides a massive resource for studying biological phenomena at single cell level. One of the most important applications of scRNA-seq is the inference of dynamic cell states through modeling of transcriptional dynamics. Understanding the full transcriptional dynamics using the concept named RNA Velocity enables us to identify cell states, regimes of regulatory changes in cell states, and putative drivers within these states. We present scRegulocity that integrates RNA-velocity estimates with locality information from cell embedding coordinates. scRegulocity focuses on velocity switching patterns, local patterns where velocity of nearby cells change abruptly. These different transcriptional dynamics patterns can be indicative of transitioning cell states. scRegulocity annotates these patterns with genes and enriched pathways and also analyzes and visualizes the velocity switching patterns at the regulatory network level. scRegulocity also combines velocity estimation, pattern detection and visualization steps.

bioinformatics↗

bioRxiv2020

A comprehensive library of fluorescent constructs of SARS-CoV-2 proteins and their initial characterization in different cell types

Comprehensive libraries of plasmids for SARS-CoV-2 proteins with various tags (e.g. Strep, HA, Turbo) are now available. They enable the identification of numerous potential protein-protein interactions between the SARS-CoV-2 virus and host proteins. To facilitate further cellular investigations, notably by imaging techniques, we present here a large library of SARS CoV-2 protein constructs fused with green and red fluorescent proteins and their initial characterization in various human cell lines including lung epithelial cell models (A549, BEAS-2B), as well as in budding yeast. The localization of a few SARS-CoV-2 proteins matches their proposed interactions with host proteins. These include the localization of Nsp13 to the centrosome, Orf3a to late endosomes, and Orf9b to mitochondria.

cell biology↗

bioRxiv2019

Molecular profiling predicts meningioma recurrence and reveals loss of DREAM complex repression in aggressive tumors

Meningiomas account for one-third of all primary brain tumors. Although typically benign, about 20% of meningiomas are aggressive, and despite the rigor of the current histopathological classification system, there remains considerable uncertainty in predicting tumor behavior. Here, we analyzed 160 tumors from all three WHO grades (I-III) using clinical, gene expression and sequencing data. Unsupervised clustering analysis identified three molecular types (A, B, and C) that reliably predicted recurrence. These groups did not directly correlate with the WHO grading system, which would classify more than half of the tumors in the most aggressive molecular type as benign. Transcriptional and biochemical analyses revealed that aggressive meningiomas involve loss of the repressor function of the DREAM complex, which results in cell cycle activation; only tumors in this category tend to recur after full resection. These findings should improve our ability to predict recurrence and develop targeted treatments for these clinically challenging tumors.\n\nSignificance StatementMeningiomas are the most common primary brain tumors. Although most of these tumors are benign, one-fifth will recur despite apparently complete resection. Several studies have demonstrated that genomic approaches can yield important insights into the biology of these tumors. We performed RNA sequencing and whole-exome sequencing of 160 tumors from 140 patients, which identified three distinct groups of meningioma that correlate with recurrence better than the current WHO grading system. Our analysis also revealed that the most aggressive type was characterized by loss of the repressive DREAM complex. These findings should improve prognostication for patients and lead to viable therapeutic targets.

cancer biology↗

bioRxiv2019

Aimed limb movements in a hemimetabolous insect are intrinsically compensated for allometric wing growth by developmental mechanisms

For aimed limb movements to remain functional they must be adapted to developmental changes in body morphology and sensory-motor systems. Insects use their limbs to groom the body surface or to dislodge external stimuli, but they face the particular problem of adapting these movements to step-like changes in body morphology during metamorphosis or moulting. Locusts are hemimetabolous insects in which the imaginal moult to adulthood results in a sudden and dramatic allometric growth of the wings relative to the body and the legs. We show that, despite this, hind limb scratches aimed at mechanosensory stimuli on the wings remain targeted to appropriate locations after moulting. In juveniles, the tips of the wings extend less than half way along the abdomen, but in adults they extend well beyond the posterior end. Kinematic analyses were used to examine the scratching responses of juveniles (5th instars) and adults to touch of anterior (wing base) and posterior (distal abdomen) targets that develop isometrically, and to wing tip targets that are anterior in juveniles but posterior in adults. Juveniles reach the (anterior) wing tip with the distal tibia of the hind leg using anterior rotation of the thoraco-coxal and coxo-trochanteral ( hip) joints and flexion of the femoro-tibial ( knee) joint. Adults, however, reach the corresponding (but now posterior) wing tip using posterior rotation of the hip and extension of the knee, reflecting a different underlying motor pattern. This change in kinematics occurs immediately after the adult moult without learning, indicating that the switch is developmentally programmed.\n\nSUMMARY STATEMENTA developmentally programmed change in the scratching movements of locusts permits adult animals to aim their movements at new wing tip targets, without learning.

neuroscience↗