Biology subjects

Steele, N.

Publications and source records attributed to Steele, N..

13 recordsLinked to original sources

bioRxiv2026

Dissociable Neural Responses to Conditioned Social Threats are Modulated by Spatial Proximity in PTSD and MDD

The brains response to potential threats is shaped by the egocentric spatiotemporal distance to the threat. While distal threats recruit evaluative, cognitive-fear networks for strategic planning, proximal threats engage evolutionarily conserved reactive-fear circuitry to mount immediate defensive responses. Understanding this dual neural architecture is clinically relevant, as the spatial proximity to a traumatic event predicts subsequent psychiatric symptom severity and recovery. Despite the well-characterized disruptions to threat circuitry in posttraumatic stress disorder (PTSD) and major depressive disorder (MDD), how these networks respond to threats at distinct spatial distances has yet to be investigated in these disorders. Utilizing 3D virtual reality technology, we implemented a spatially-modulated fear conditioning paradigm by presenting human avatars at proximal (peripersonal) and distal (extrapersonal) distances, paired with shock, to trauma-exposed participants (n = 50) during functional MRI (fMRI). We modeled associations between PTSD and MDD symptom severity and task-evoked hemodynamic responses within cognitive-fear and reactive-fear threat networks. Our results support a transdiagnostic disruption of thalamic responses to proximal threats, driven by heightened activation to the safety stimulus and stronger deactivation to the threat stimulus. MDD showed a disorder-specific effect of disrupted activity across cognitive-fear and social cognition regions in response to proximal social threats, and illness severity-by-proximity effects across motor regions. PTSD symptom severity was uniquely associated with hyperactivity of the amygdala to distal threats. Transdiagnostic disruption of connectivity between the dorsal precuneus and several subcortical structures followed a disorder-specific gradient across the anterior-posterior axis. While thalamic disruptions to threats represent a shared transdiagnostic effect, PTSD and MDD are distinguished by differences in amygdala hyperactivation and cognitive-fear network hypoactivation, respectively.

neuroscience↗

bioRxiv2026

A targetable opioid/cancer associated fibroblast axis drives extracellular matrix remodeling and tumor aggressiveness in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is an intractable disease with few effective treatment options. PDAC is characterized by a dense, fibro-inflammatory tumor microenvironment (TME) consisting mainly of cancer-associated fibroblasts (CAFs) and a CAF-generated collagen-rich extracellular matrix (ECM). As the ECM has profound impacts on tumor progression and therapy response, it is critical that we understand the mechanisms underlying ECM deposition and remodeling. In addition to a highly fibrotic and reactive TME, a hallmark of PDAC is pain. 93% of PDAC patients experience pain, and [~]70% are prescribed opioids for pain management during the course of their cancer treatment. Despite epidemiological evidence linking opioid use with diminished patient survival, how opioids impact tumor biology remains largely unknown. We now provide evidence that both endogenous and exogenous opioids drive ECM remodeling in the PDAC TME. We find that the commonly prescribed opioid morphine promotes the development of poorly differentiated tumors and increases collagen bundling and maturation in a mouse model of PDAC. Accordingly, RNA sequencing reveals that morphine induces significant upregulation of ECM genes and collagen modifying enzymes. We developed a morphine-induced gene signature which correlates significantly with the basal/mesenchymal subtypes of human PDAC and predicts worse overall survival in PDAC and other tumor types. Mechanistically, pharmacological inhibition and genetic knockdown of the mu opioid receptor (OPRM1) in CAFs attenuates expression of type 1a and type 3a collagens, and the myofibroblastic CAF marker alpha-SMA, demonstrating that opioid signaling is a direct regulator of CAF biology. Additionally, we provide the first evidence that CAFs produce endogenous opioids capable of activating OPRM1 and driving collagen expression. Finally, treatment with the FDA-approved peripherally restricted OPRM1 antagonist methylnaltrexone (MNTX) reduces desmoplasia, tumor weight, and ascites burden in a mouse model of PDAC. Therefore, we have identified a novel opioid-mediated signaling axis driving PDAC desmoplasia and reveal MNTX as a potential therapeutic to inhibit both exogenous and endogenous opioid-induced ECM remodeling and tumor aggressiveness.

cancer biology↗

bioRxiv2026

Extra-lineage tissue programs define the transcription states of human pancreatic cancer

Cancers acquire alternate transcriptional states as they evolve, but the origins, timing and determinants of this plasticity are poorly understood in many tumours. We investigated the transcriptional states of pancreatic cancer by integrating [~]1000 tumour-enriched genomes and transcriptomes from 464 patients combined with scRNA-seq, multiome profiling, and spatial proteomics. Four epithelial states covering the spectrum of lineage plasticity were identified (Classical-1, Classical-2, Basal-1, Basal-2). Comparing these states to normal and pan-cancer human single cell atlases showed each state reflects distinct tissue programs found in other malignancies. Single cell analysis uncovered that the main transcription state of this disease (Classical-1) emerges before KRAS mutations. Spatial proteomics from patients and cancer-free donors showed that the Classical-1 program emerges during acinar-to-ductal metaplasia, and also unexpectedly, in normal ducts without disrupting their morphology. Overall, these findings link the extensive lineage plasticity potential of this organ to the origins of the transcriptional states.

cancer biology↗

bioRxiv2025

Comparative Analysis of Primary and Liver Fibroblasts Reveals MET as a Potent Target in Pancreatic Cancer Metastasis

The tumor microenvironment drives many malignant features of pancreatic ductal adenocarcinoma (PDAC). The fibroblasts within pancreatic tumors promote tissue remodeling, immune suppression, and resistance to therapy. However, the interactions between stromal populations and pancreatic cancer cells are less understood in the liver, the most frequent site of PDAC metastasis. To address this, we employ single cell transcriptomics to compare primary pancreatic vs. liver PDAC lesions. Here, we identify the expression of hepatocyte growth factor (HGF) in fibroblasts and its receptor MET in cancer cells are both markedly increased in the PDAC liver niche. Using functional assays, we validate that mitogenic MET signaling is activated in PDAC cells by liver-derived fibroblasts. Importantly, the inhibition of MET signaling leads to reduced tumor growth in immune competent mouse models. Collectively, our data demonstrates that liver stromal-epithelial crosstalk networks engage in signaling pathways distinct from primary pancreatic tumors, highlighting opportunities to develop new treatments for metastatic disease.

cancer biology↗

bioRxiv2025

TESSA: A unified model to detect trajectory-preserved and spatially-variable genes in spatial transcriptomics

Identifying spatially variable genes (SVGs) has been an essential task in spatial transcriptomics. In addition to SVGs detection, there are genes exhibiting expression patterns that are associated with cellular developmental stages or lineage fates across a tissue section. Identifying such genes could provide novel insights into tumor metastasis. Here, we introduce a unified statistical model, termed TrajEctory-preServed and SpAtially-variable gene detection (TESSA), to detect both types of genes. Moreover, we propose a novel strategy to address the inherent double-dipping issue commonly encountered when assessing temporal gene effects in transcriptomics analysis. We demonstrate the testing performance through extensive simulation studies and real applications to several publicly available datasets. Downstream analyses further highlight the potential of our method in identifying genes associated with tumor progression and enhancing spatial domain detection.

bioinformatics↗

bioRxiv2025

Volumetric Differences of Thalamic Nuclei are Associated with Post-Trauma Psychopathology

Previous investigations of whole thalamus and thalamic nuclei volumes in post-trauma psychopathology have been sparse, limited in scope, and yielded inconsistent results. To address this, volumetric estimates of whole thalamus and thalamic nuclei were obtained from structural brain MRI scans from 2,058 participants across 20 worldwide sites in the ENIGMA PTSD working group. Thalamic volumes were compared between trauma-exposed participants with posttraumatic stress disorder (PTSD) (n=238), major depressive disorder (MDD) (n=184), comorbid PTSD+MDD (n=618), and trauma-exposed control participants (n=1,018). PTSD and MDD symptom severity, PTSD symptom clusters, and childhood trauma were similarly examined for associations with thalamic volume. Participants with PTSD only compared to controls had smaller thalamic nuclei volumes in sensorimotor nuclei, including the parafascicular (Pf), ventral anterior magnocellular (VAmc), medial pulvinar (PuM), and anterior pulvinar (PuA) nuclei of the thalamus. MDD only and comorbid PTSD+MDD participants exhibited smaller mediodorsal thalamus volumes compared to controls. Overall PTSD and MDD symptom severity negatively correlated with the volume of the mediodorsal thalamus. A significant interaction between PTSD and MDD severity was found, such that MDD severity was positively associated with thalamic volume only among individuals with high PTSD severity. Avoidance and hyperarousal symptoms of PTSD were positively associated with thalamic volume, while re- experiencing and negative mood/cognition symptoms were negatively associated with thalamic volume. Childhood physical and emotional abuse were positively and negatively associated with thalamic volume, respectively. Whole thalamus volume and volumes of the sensorimotor and limbic thalamus may play an important role in the development of PTSD and MDD in the aftermath of trauma exposure. The interaction between PTSD and MDD symptoms and contrasting effects across PTSD symptom clusters and types of childhood adversity suggests multiple neurobiological mechanisms are involved in shaping thalamic volume post-trauma.

neuroscience↗

bioRxiv2025

Image-Based Meta- and Mega-Analysis (IBMMA): A Unified Framework for Large-Scale, Multi-Site, Neuroimaging Data Analysis

The increasing scale and complexity of neuroimaging datasets aggregated from multiple study sites present substantial analytic challenges, as existing statistical analysis tools struggle to handle missing voxel-data, suffer from limited computational speed and inefficient memory allocation, and are restricted in the types of statistical designs they are able to model. We introduce Image-Based Meta- & Mega-Analysis (IBMMA), a novel software package implemented in R and Python that provides a unified framework for analyzing diverse neuroimaging features, efficiently handles large-scale datasets through parallel processing, offers flexible statistical modeling options, and properly manages missing voxel-data commonly encountered in multi-site studies. IBMMA produced stronger effect sizes and revealed findings in brain regions that traditional software overlooked due to missing voxel-data resulting in gaps in brain coverage. IBMMA has the potential to accelerate discoveries in neuroscience and enhance the clinical utility of neuroimaging findings.

neuroscience↗

bioRxiv2023

ROR2 regulates cellular plasticity in pancreatic neoplasia and adenocarcinoma

Cellular plasticity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) starting from the conversion of normal cells into precancerous lesions to the progression of carcinoma subtypes associated with aggressiveness and therapeutic response. We discovered that normal acinar cell differentiation, maintained by the transcription factor Pdx1, suppresses a broad gastric cell identity that is maintained in metaplasia, neoplasia, and the classical subtype of PDAC in mouse and human. We have identified the receptor tyrosine kinase Ror2 as marker of a gastric metaplasia (SPEM)-like identity in the pancreas. Ablation of Ror2 in a mouse model of pancreatic tumorigenesis promoted a switch to a gastric pit cell identity that largely persisted through progression to the classical subtype of PDAC. In both human and mouse pancreatic cancer, ROR2 activity continued to antagonize the gastric pit cell identity, strongly promoting an epithelial to mesenchymal transition, conferring resistance to KRAS inhibition, and vulnerability to AKT inhibition. SignificanceWe discovered the receptor tyrosine kinase ROR2 as an important regulator of cellular identity in pancreatic precancerous lesions and pancreatic cancer. ROR2 drives an aggressive PDAC phenotype and confers resistance to Kras inhibitors, suggesting that targeting ROR2 will enhance sensitivity to this new generation of targeted therapies.

cancer biology↗

bioRxiv2021

Multi-omic Characterization of Pancreatic Cancer-Associated Macrophage Polarization Reveals Deregulated Metabolic Programs Driven by the GMCSF-PI3K Pathway

The pancreatic ductal adenocarcinoma (PDA) microenvironment is composed of a variety of cell types and marked by extensive fibrosis and inflammation. Tumor-associated macrophages (TAM) are abundant, and they are important mediators of disease progression and invasion. TAMs are polarized in situ to a tumor promoting and immunosuppressive phenotype via cytokine signaling and metabolic crosstalk from malignant epithelial cells and other components of the tumor microenvironment (TME). However, the specific distinguishing features and functions of TAMs remain poorly defined. Here, we generated tumor-educated macrophages (TEM) in vitro and performed detailed, multi-omic characterization (i.e. transcriptomics, proteomics, metabolomics). Our results reveal unique genetic and metabolic signatures of TEMs, the veracity of which were queried against our in-house single cell RNA sequencing (scRNA-seq) dataset of human pancreatic tumors. This analysis identified expression of novel, metabolic TEM markers in human pancreatic TAMs, including ARG1, ACLY, and TXNIP. We then utilized our TEM model system to study the role of mutant Kras signaling in cancer cells on TEM polarization. This revealed an important role for GM-CSF and lactate on TEM polarization, molecules released from cancer cells in a mutant Kras-dependent manner. Lastly, we demonstrate that GM-CSF dysregulates TEM gene expression and metabolism through PI3K-AKT pathway signaling. Collectively, our results define new markers and programs to classify pancreatic TAMs, how these are engaged by cancer cells, and the precise signaling pathways mediating polarization.

cancer biology↗

bioRxiv2021

Multi-dimensional analyses identify genes of high priority for pancreatic cancer research

Genomic profiling has unveiled the molecular subtypes and mutational landscape of pancreatic ductal adenocarcinoma (PDAC). However, there is a knowledge gap on the consistency of gene expression across PDAC tumors profiled in independent studies and this limits follow up research. To facilitate novel drug target prioritization and biomarker discovery, we investigated the most consistently expressed genes in human PDAC. We identified ~4,000 genes highly or lowly expressed in at least 4 of 5 microarrays (adjusted P<0.05) and validated their expression pattern in additional datasets, bulk tumor and single-cell RNA sequencing samples. Over 50% of the genes were previously uncharacterized in PDAC; many correlated with proliferation, metastasis, mutation, tumor grade, and ~41% predicted overall survival. We identified 185 high-priority targets (notably in cell cycle and glycolysis) whose inhibition suppressed PDAC cell viability in multiple RNA interference datasets and these genes predicted treatment in mouse models. Our results represent important milestone in the quest for mechanisms, drug targets and biomarkers in PDAC, and originate from an adaptable analytical concept that can aid discovery in other cancers. HighlightsO_LIIdentifies ~4,000 consistent genes across PDAC microarrays, >50% of which have not been studied C_LIO_LIGlycolysis and cell cycle are the most consistent processes in PDAC C_LIO_LIHeterogeneous pathways underlie or correlate with clinicopathological variables C_LIO_LIIdentifies 205 genes with similar expression pattern in PDAC tissues and peripheral blood C_LIO_LIHighlights 185 upregulated genes that are high priority therapeutic targets in PDAC C_LI

cancer biology↗

bioRxiv2020

Gastric metabolomics analysis supports H. pyloris catabolism of organic and amino acids in both the corpus and antrum

Helicobacter pylori is a chronic bacterial pathogen that thrives in several regions of the stomach, causing inflammation that can vary by site and result in distinct disease outcomes. It is not known, however, whether the host-derived metabolites differ between the two main regions, the corpus and antrum. We thus characterized the metabolomes of mouse gastric corpus and antrum organoids and tissue. The secreted organoid metabolites differed significantly between the corpus and antrum in only seven metabolites: lactic acid, malic acid, phosphoethanolamine, alanine, uridine, glycerol, and isoleucine, with only lactic acid and phosphoethanolamine exceeding two-fold differences. Multiple chemicals were depleted upon H. pylori infection including urea, cholesterol, glutamine, fumaric acid, lactic acid, citric acid, malic acid, and multiple non-essential amino acids. Many are known H. pylori nutrients and did not differ between the two regions. When tissue was examined, there was little overlap with the organoid metabolites. The two tissue regions were distinct, however, including in antrum-elevated 5-methoxytryptamine, lactic acid, and caprylic acid, and corpus-elevated phospholipid products. Over an 8 month infection time course, the corpus and antrum remained distinct. The antrum displayed no significant changes, in contrast to the corpus which exhibited metabolite changes indicating stress, tissue damage, and depletion of key nutrients such as glutamine and fructose-6-phosphate. Overall, our results suggest the H. pylori preferentially uses carboxylic acids and amino acids in complex environments, and these are found in both the corpus and antrum.

microbiology↗

bioRxiv2020

Loss of Activating Transcription Factor 3 prevents KRAS-mediated pancreatic cancer

The unfolded protein response (UPR) is activated in pancreatic pathologies and suggested as a target for therapeutic intervention. In this study, wxe examined Activating Transcription Factor 3 (ATF3), a mediator of the UPR which promotes acinar-to-ductal metaplasia (ADM) in response to pancreatic injury. Since ADM is an initial step in the progression to pancreatic ductal adenocarcinoma (PDAC), we hypothesized ATF3 is required for initiation and progression of PDAC. We generated mice carrying a germ line mutation of Atf3 (Atf3-/-) combined with acinar-specific induction of oncogenic KRAS (Ptf1acreERT/+KrasLSL-G12D). Atf3-/- mice with (termed APK) and without KRASG12D were exposed to cerulein-induced pancreatitis. In response to recurrent pancreatitis, Atf3-/- mice showed decreased ADM and enhanced regeneration based on morphological and biochemical analysis. Similarly, an absence of ATF3 reduced spontaneous pancreatic intraepithelial neoplasia formation and PDAC in Ptf1acreERT/+KrasLSL-G12D mice. In response to injury, KRASG12D bipassed the requirement for ATF3 with a dramatic loss in acinar tissue and PanIN formation observed regardless of ATF3 status. However, unlike Ptf1acreERT/+KrasLSL-G12D mice, APK mice exhibited a cachexia-like phenotype, did not progress through to PDAC, and showed altered pancreatic fibrosis and immune cell infiltration. These findings suggest a complex, multifaceted role for ATF3 in pancreatic cancer pathology.

cancer biology↗

bioRxiv2019

Beta 1 Integrin Signaling Mediates Pancreatic Ductal Adenocarcinoma Resistance to MEK Inhibition

Pancreatic cancer, one of the deadliest human malignancies, has a dismal 5-year survival rate of 9%. The high mortality rate can be attributed to multiple factors, including late diagnosis and lack of effective therapies. KRAS is the most commonly mutated gene in pancreatic cancer, but clinical agents that directly target mutant KRAS are not available. Several effector pathways are activated downstream of oncogenic Kras, including MAPK signaling. MAPK signaling can be inhibited by targeting MEK1/2; unfortunately, this approach has been largely ineffective in pancreatic cancer. Here, we set out to identify mechanisms of MEK inhibitor resistance in pancreatic cancer using primary mouse and human 3D organoid cultures. We optimized the culture of pancreatic tumor organoids that utilized Matrigel as a basement membrane mimetic, facilitating polarized growth. Pancreatic tumor organoids recapitulated mutant KRAS dependency and recalcitrance to MEK inhibition. Treatment of the organoids with trametinib, a MEK inhibitor, had only a modest effect on these cultures. We observed that cells adjacent to the basement membrane mimetic Matrigel survived MEK inhibition, while the cells in the interior layers underwent apoptosis. Our findings suggested that basement membrane attachment provided survival signals. We thus targeted integrin {beta}1, a mediator of extracellular matrix contact, and found that combined MEK and integrin {beta}1 inhibition bypassed trametinib resistance. Our data support exploring integrin signaling inhibition as a component of combination therapy in pancreatic cancer.

cancer biology↗