Biology subjects

Sammons, M.

Publications and source records attributed to Sammons, M..

8 recordsLinked to original sources

bioRxiv2026

Structure-Function Analysis of an Infantile Rhabdomyosarcoma Fusion-Oncogene Reveals Domain Requirements for Tumorigenesis

Rhabdomyosarcoma is a pediatric soft-tissue sarcoma that reflects impaired skeletal muscle differentiation. Spindle cell/sclerosing rhabdomyosarcoma is a histological subtype found in children and adults. In children under two, spindle cell rhabdomyosarcoma is genetically driven by fusion-oncogenes of transcription factors or co-activators important for skeletal muscle lineage commitment and development. The most common fusion-oncogene in this group is VGLL2::NCOA2, a fusion between vestigial-like family member 2 (VGLL2) and nuclear receptor coactivator 2 (NCOA2). Children with fusion-driven rhabdomyosarcoma are treated with general chemotherapy, surgery, and radiation, which are not specific to the molecular underpinnings, and increase risk of secondary malignancies and premature death. Previously, we showed that VGLL2::NCOA2 is transforming in mouse myoblasts and transgenic zebrafish tumor models. Here, we build on this work by detailing the structure-function relationship of the retained VGLL2::NCOA2 protein domains to define domain requirements and their molecular interactions for tumorigenesis. We created deletion mutants of the VGLL2 vestigial/Tondu (TDU) domain and the NCOA2 activating domains 1 and 2 (AD1 and AD2), and a double mutant lacking the TDU+AD1 domains and assessed their function in a mouse myoblast model. We find that the TDU and AD1 domains support nuclear fusion-oncogene localization, transformation in vitro, and tumorigenesis in a mouse allograft model. Furthermore, transcriptomic analysis demonstrates that the TDU or AD1 mutant VGLL2::NCOA2 drives an upregulation of myogenesis gene sets and supports terminal differentiation. Overall, our results indicate that VGLL2::NCOA2 requires the TDU and AD1 domains for optimal transformation, and that targeting these domains, or their interacting protein partners, represents a therapeutic opportunity.

cancer biology↗

bioRxiv2026

Pain Matters: Nociceptive signaling drives neural encoding of inflammatory responses

Pain is a cardinal sign of inflammation, constructed by the brain from peripheral nociceptive input. Yet, its role in the brain's response to inflammation remains unknown. Here, we demonstrate that nociceptive signaling is essential for the brain to represent and replay inflammatory states. Analysis of human fMRI and mouse activity mapping revealed that peripheral inflammation generates a distinct brain state. In mice, ablation of TRPV1+ sensory neurons or pharmacological analgesia disrupted this organization and prevented the insular cortex from forming retrievable immune representations. Conversely, augmenting nociceptive signaling during inflammation strengthened subsequent immune recall. These findings identify nociceptive input as a critical signal in brain-immune dialogue, enabling the encoding and retrieval of inflammatory events.

neuroscience↗

bioRxiv2026

SCANBIT facilitates identification of tumor cell populations in scRNAseq data using pseudobulked SNV calls

MotivationSingle cell RNAseq (scRNAseq) is an ideal tool to characterize the heterogeneity within the tumor microenvironment, however, accurate identification of tumor cells can be a challenge. Reference-based methods can be inaccurate, if reference datasets are even available. Current purpose-built methods can be inaccurate, particularly with highly heterogeneous tumor types. Improved methods are needed. We explored the use of genetic variants to distinguish tumor from normal cells within scRNAseq data. ResultsWe characterized the limitations inherent to calling variants from scRNAseq data, quantifying how data sparsity precludes genetic distance calculation between single cells. As a novel workaround, we pooled data from transcriptionally similar cell clusters to call high quality variants and then calculated pairwise differences between cell populations and performed hierarchical clustering. We quantified confidence in genetic divergence between tumor and normal cell populations using bootstrapping. We performed extensive validation to assess accurate identification of tumor cells using ground-truth datasets. Application of our method to human scRNAseq samples highlighted the utility of our approach and revealed how mutational burden influences successful tumor cell identification. Improved cell type assignment in scRNAseq data will facilitate analysis of tumor samples and, in turn, accelerate our understanding of the mechanisms underlying tumor progression and reveal potential biological vulnerabilities that can be exploited to develop improved treatment options. Availability and implementationOur method is publicly available as an R package: SCANBIT (Single Cell Altered Nucleotide Based Inference of Tumor) https://github.com/kidcancerlab/scanBit.

bioinformatics↗

bioRxiv2025

NR0B1 alters the 9-cis-retinoic acid response in Ewing Sarcoma cells

Pediatric cancers are often characterized by relatively low DNA mutation rates and are frequently driven instead by alterations in gene expression programs. In Ewing Sarcoma (EwS), these changes result from the activity of an oncogenic fusion transcription factor, EWS::FLI1, which alters the enhancer landscape and rewires transcriptional programs to promote oncogenic transformation. Among the targets directly activated by EWS::FLI1, NR0B1 has emerged as a potentially targetable transcription co-regulator and as a manifold for widespread alterations in downstream gene expression programs mediated by members of the ligand-inducible nuclear receptor superfamily of transcription factors. We have dissected the gene regulatory activity of NR0B1 in EwS models, showing its role in altering the basal gene expression programs of nuclear receptors COUP-TFII, EAR2, RXRa, and TR4. Additionally, we show that NR0B1 impacts the EwS response to retinoids, particularly 9-cis-retinoic acid signaling in part through RXRa. Our findings suggest NR0B1 silencing or inhibition offer a means of achieving a more potent response to retinoids, which may activate differentiation programs, decrease EwS gene expression signatures, and limit in vitro transformation phenotypes. Taken together, our study presents evidence of NR0B1 acting canonically as a nuclear receptor co-regulator in EwS, revealing a potential pathway to treatment of this aggressive cancer by combining NR0B1 inhibition with therapeutic nuclear receptor ligands.

cancer biology↗

bioRxiv2023

Driver lines for studying associative learning in Drosophila

AbstractThe mushroom body (MB) is the center for associative learning in insects. In Drosophila, intersectional split-GAL4 drivers and electron microscopy (EM) connectomes have laid the foundation for precise interrogation of the MB neural circuits. However, investigation of many cell types upstream and downstream of the MB has been hindered due to lack of specific driver lines. Here we describe a new collection of over 800 split-GAL4 and split-LexA drivers that cover approximately 300 cell types, including sugar sensory neurons, putative nociceptive ascending neurons, olfactory and thermo-/hygro-sensory projection neurons, interneurons connected with the MB-extrinsic neurons, and various other cell types. We characterized activation phenotypes for a subset of these lines and identified a sugar sensory neuron line most suitable for reward substitution. Leveraging the thousands of confocal microscopy images associated with the collection, we analyzed neuronal morphological stereotypy and discovered that one set of mushroom body output neurons, MBON08/MBON09, exhibits striking individuality and asymmetry across animals. In conjunction with the EM connectome maps, the driver lines reported here offer a powerful resource for functional dissection of neural circuits for associative learning in adult Drosophila.

neuroscience↗

bioRxiv2022

Neural circuit mechanisms for transforming learned olfactory valences into wind-oriented movement

How memories are used by the brain to guide future action is poorly understood. In olfactory associative learning in Drosophila, multiple compartments of the mushroom body act in parallel to assign valence to a stimulus. Here, we show that appetitive memories stored in different compartments induce different levels of upwind locomotion. Using a photoactivation screen of a new collection of split-GAL4 drivers and EM connectomics, we identified a cluster of neurons postsynaptic to the mushroom body output neurons (MBONs) that can trigger robust upwind steering. These UpWind Neurons (UpWiNs) integrate inhibitory and excitatory synaptic inputs from MBONs of appetitive and aversive memory compartments, respectively. After training, disinhibition from the appetitive-memory MBONs enhances the response of UpWiNs to reward-predicting odors. Blocking UpWiNs impaired appetitive memory and reduced upwind locomotion during retrieval. Photoactivation of UpWiNs also increased the chance of returning to a location where activation was initiated, suggesting an additional role in olfactory navigation. Thus, our results provide insight into how learned abstract valences are gradually transformed into concrete memory-driven actions through divergent and convergent networks, a neuronal architecture that is commonly found in the vertebrate and invertebrate brains.

neuroscience↗

bioRxiv2022

Hierarchical architecture of dopaminergic circuits enables second-order conditioning in Drosophila

Dopaminergic neurons with distinct projection patterns and physiological properties compose memory subsystems in a brain. However, it is poorly understood whether or how they interact during complex learning. Here, we identify a feedforward circuit formed between dopamine subsystems and show that it is essential for second-order conditioning, an ethologically important form of higher-order associative learning. The Drosophila mushroom body comprises a series of dopaminergic compartments, each of which exhibits distinct memory dynamics. We find that a slow and stable memory compartment can serve as an effective "teacher" by instructing other faster and transient memory compartments via a single key interneuron, which we identify by connectome analysis and neurotransmitter prediction. This excitatory interneuron acquires enhanced response to reward-predicting odor after first-order conditioning and, upon activation, evokes dopamine release in the "student" compartments. These hierarchical connections between dopamine subsystems explain distinct properties of first- and second-order memory long known by behavioral psychologists.

neuroscience↗

bioRxiv2019

Smad4 signaling establishes the somatosensory map of basal vomeronasal sensory neurons

The accessory olfactory system is a unique model that can give insights on how the neurons can establish and maintain their identity, and connectivity. The vomeronasal organ (VNO) contains two distinct populations of vomeronasal sensory neurons (VSNs) each with specific innervation patterns to the accessory olfactory bulb (AOB). Though morphogenic signals are critical in defining various neuronal populations, the morphogenic signaling profiles that influence each VSN population remains unknown. Here, we found a pronounced BMP signaling gradient within the basal VSNs. By generating Smad4 conditional mutants, we disrupted canonical TGF-{beta}/BMP signaling in maturing basal VSNs and in all mature VSNs. We show that Smad4 loss-of-function in immature basal neurons leads to a progressive loss of basal VSNs, reduced activation of the remnant basal VSNs, and aberrant glomeruli formation in posterior AOB. However, Smad4 ablation in all mature VSNs does not affect neuronal activity nor survival but causes aberrant glomeruli formation only in the posterior AOB. Our study reveals that Smad4 signaling plays a critical role in mediating development, function, and circuit formation of basal VSNs.

developmental biology↗