Biology subjects

Officer, A.

Publications and source records attributed to Officer, A..

10 recordsLinked to original sources

bioRxiv2026

spatiAlytica: Viewer-Grounded Multimodal Agentic System for Interactive Spatial Omics Analysis

Spatial transcriptomics and proteomics map tissue architecture and cellular interactions, but analysis remains limited by programming demands and text-centered AI agents that lack viewer grounding and cross-turn context. We present spatiAlytica, a viewer-centric multimodal interactive agentic system embedded in the Napari viewer that enables non-programmer biologists to perform iterative, hypothesis-driven spatial omics analysis via natural language. spatiAlytica couples viewer-state serialization, agentic memory, biological concept-to-data-field mapping, code generation and debugging, Spatial VQA, and grounded interpretation to support an exploratory analysis and interpretive reasoning workflow. We introduce spatiAlyticaBench, a comprehensive benchmark spanning 222 single-turn spatial analytical coding questions, 178 multi-turn sequential workflow questions, and 7,350 image-grounded reasoning questions. spatiAlytica outperformed strong agentic baselines, while using less time and tokens. Case studies across Kaposis sarcoma, colorectal cancer, and ovarian cancer recapitulated known spatial patterns and uncovered progressive CD8 T-cell dysfunction during KS progression.

bioinformatics↗

bioRxiv2025

A predisposing effect of HLA class II genes in celiac disease by skewing the naive CD4+ T-cell receptor repertoire

Polymorphisms of human leukocyte antigen (HLA) genes confer risks for many human diseases. For predisposing effects relating to T-cell receptor (TCR) recognition of peptide-HLA, the effect can be both selection of the TCR repertoire and preferential presentation of disease-driving epitopes. In celiac disease (CeD) HLA-DQ2.5 predisposes by presenting deamidated gluten peptides to CD4+ T cells that typically employ stereotyped TCRs. Here we analyzed whether genetic variants within the HLA and TR loci shape the naive TCR repertoire. We sequenced the {beta} TCR repertoires of naive CD4+ T cells of 103 CeD subjects and 103 controls and performed gene usage quantitative trait loci analyses. The naive CD4+ TCR repertoire was significantly affected by HLA and TRA and TRB polymorphisms. Individuals carrying the HLA-DQ2.5 allotype exhibited increased frequencies of TCR genes involved in stereotyped recognition of gluten epitopes thus demonstrating a disease-predisposing effect of HLA by selection of a disease-relevant TCR repertoire.

immunology↗

bioRxiv2023

Tumor microenvironmental determinants of high-risk DCIS progression

ABSTRACT/SUMMARYDuctal carcinoma in situ (DCIS) constitutes an array of morphologically recognized intraductal neoplasms in the mammary ductal tree defined by an increased risk for subsequent invasive carcinomas at or near the site of biopsy detection. However, only 15-45% of untreated DCIS cases progress to invasive cancer, so understanding mechanisms that prevent progression is key to avoid overtreatment and provides a basis for alternative therapies and prevention. This study was designed to characterize the tumor microenvironment and molecular profile of high-risk DCIS that grew to a large size but remained as DCIS. All patients had DCIS lesions >5cm in size with at least one additional high-risk feature: young age (<45 years), high nuclear grade, hormone receptor negativity, HER2 positivity, the presence of comedonecrosis, or a palpable mass. The tumor immune microenvironment was characterized using multiplex immunofluorescence to identify immune cells and their spatial relationships within the ducts and stroma. Gene copy number analysis and whole exome DNA sequencing identified the mutational burden and driver mutations, and quantitative whole-transcriptome/gene expression analyses were performed. There was no association between the percent of the DCIS genome characterized by copy number variants (CNAs) and recurrence events (DCIS or invasive). Mutations, especially missense mutations, in the breast cancer driver genes PIK3CA and TP53 were common in this high-risk DCIS cohort (47% of evaluated lesions). Tumor infiltrating lymphocyte (TIL) density was higher in DCIS lesions with TP53 mutations (p=0.0079) compared to wildtype lesions, but not in lesions with PIK3CA mutations (p=0.44). Immune infiltrates were negatively associated with hormone receptor status and positively associated with HER2 expression. High levels of CD3+CD8-T cells were associated with good outcomes with respect to any subsequent recurrence (DCIS or invasive cancer), whereas high levels of CD3+Foxp3+ Treg cells were associated with poor outcomes. Spatial proximity analyses of immune cells and tumor cells demonstrated that close proximity of T cells with tumor cells was associated with good outcomes with respect to any recurrence as well as invasive recurrences. Interestingly, we found that myoepithelial continuity (distance between myoepithelial cells surrounding the involved ducts) was significantly lower in DCIS lesions compared to normal tissue (p=0.0002) or to atypical ductal hyperplasia (p=0.011). Gene set enrichment analysis identified several immune pathways associated with low myoepithelial continuity and a low myoepithelial continuity score was associated with better outcomes, suggesting that gaps in the myoepithelial layer may allow access/interactions between immune infiltrates and tumor cells. Our study demonstrates the immune microenvironment of DCIS, in particular the spatial proximity of tumor cells and T cells, and myoepithelial continuity are important determinants for progression of disease.

cancer biology↗

bioRxiv2023

Direct reprogramming of oral epithelial progenitor cells to cancer stem cells at single cell resolution in vivo

Tumor initiation represents the first step in tumorigenesis during which normal progenitor cells undergo cell fate transition to cancer. Capturing this process as it occurs in vivo, however, remains elusive. Here we employ spatiotemporally controlled oncogene activation and tumor suppressor inhibition together with multiomics to unveil the processes underlying oral epithelial progenitor cell reprogramming into tumor initiating cells (TIC) at single cell resolution. TIC displayed a distinct stem-like state, defined by aberrant proliferative, hypoxic, squamous differentiation, and partial epithelial to mesenchymal (pEMT) invasive gene programs. YAP-mediated TIC programs included the activation of oncogenic transcriptional networks and mTOR signaling, and the recruitment of myeloid cells to the invasive front contributing to tumor infiltration. TIC transcriptional programs are conserved in human head and neck cancer and associated with poor patient survival. These findings illuminate processes underlying cancer initiation at single cell resolution, and identify candidate targets for early cancer detection and prevention.

cancer biology↗

bioRxiv2022

Integrated Molecular Characterization of Intraductal Papillary Mucinous Neoplasms: An NCI Cancer Moonshot Precancer Atlas Pilot Project

Intraductal papillary mucinous neoplasms (IPMNs) are cystic precursor lesions to pancreatic ductal adenocarcinoma (PDAC). IPMNs undergo multistep progression from low grade (LG) to high grade (HG) dysplasia, culminating in invasive neoplasia. While patterns of IPMN progression have been analyzed using multi-region sequencing for somatic mutations, there is no integrated assessment of molecular events, including copy number alterations (CNAs) and transcriptomics changes, that accompany IPMN progression. We performed laser capture microdissection on surgically resected IPMNs of varying grades of histological dysplasia obtained from 24 patients (total of 74 independent histological lesions), followed by whole exome and whole transcriptome sequencing. Overall, HG IPMNs displayed a significantly greater aneuploidy score than LG lesions, with chromosome 1q amplification, in particular, being associated with HG progression and with cases that harbored cooccurring PDAC. Furthermore, the combined assessment of single nucleotide variants (SNVs) and CNAs identified both linear and branched evolutionary trajectories, underscoring the heterogeneity in the progression of LG lesions to HG and PDAC. At the transcriptome level, upregulation of MYC-regulated targets and downregulation of transcripts associated with the MHC class I antigen presentation machinery was a common feature of progression to HG. Taken together, this work emphasizes the role of 1q copy number amplification as a putative biomarker of high-risk IPMNs, underscores the importance of immune evasion even in non-invasive precursor lesions, and supports a previously underappreciated role of CNA-driven branching evolution as an avenue for IPMN progression. Our study provides important molecular context for risk stratification and cancer interception opportunities in IPMNs. SignificanceIntegrated molecular analysis of genomic and transcriptomic alterations in the multistep progression of intraductal papillary mucinous neoplasms (IPMNs), which are bona fide precursors of pancreatic cancer, identifies features associated with progression of low-risk lesions to high-risk lesions and cancer, which might enable patient stratification and cancer interception strategies.

cancer biology↗

bioRxiv2022

Differential Analysis of Stromal-Epithelial Interactions between In Situ and Invasive Breast Cancer using Gene Expression Profiling

BackgroundChanges in microenvironment cell-cell interactions (CCI) during the progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) are poorly understood. Gene expression studies are confounded by cellular heterogeneity and few separate stromal and epithelial contributions, resulting in a lack of reliable prognostic biomarker to guide treatment decisions. MethodsThe gene expression of 293 microdissected regions from DCIS (92 epithelial, 31 stromal) and IDC (78 epithelial, 30 stromal) cases was aggregated from 6 datasets. Expression signatures of 6 cell lineages extracted from normal breast single-cell profiling were used to correct for differences in cell abundance. Subtype-specific functional differences between DCIS and IDC were measured for each region type using Gene Set Enrichment Analysis (GSEA). DCIS-IDC stromal-epithelial interactions were compared using the expression product of 139 ligand-receptor (LR) pairs permuting the DCIS-IDC labels to assess significance. ResultsVariation in cell-lineage abundance separated epithelial regions into 4 clusters, including one enriched for DCIS (Myoepi-Enriched) and two for IDC (Infiltrated, Vascularized). GSEA on cell lineage normalized expression data identified subtype-independent changes in epithelial regions (induction of Extracellular Matrix maintenance genes, reduction of Tp53 signaling in IDC), as well as subtype-specific changes (proliferation in ER- and Her2-IDC, reduction in Nucleotide Excision Repair in ER+ IDC). In the stroma, Notch and Rho-GTPase signaling were induced in IDC irrespective of subtype. The stromal-epithelial interaction level of 6 and 4 LR pairs were significantly enriched in DCIS and IDC, respectively. Five of the 6 DCIS-enriched LR pairs involved ephrin interactions, with interaction level progressively decreasing from normal to DCIS to IDC. In contrast, 2 IDC-enriched LR pairs involved T-cell activity likely regulating Treg proliferation (CD28-CD86) or T and NK cells stimulation (CD226-PVR). Notably, the bulk expression product of one identified LR pair (EPHB4-EFNB1) was associated with poor survival in IDC (HR=1.47, p=0.04) suggesting that early remodeling of this stromal-epithelial interaction may have long-lasting impact on disease severity. ConclusionsThe observed changes in cell states and stromal-epithelial interactions, beyond those driven by difference in cell abundance, may lead to new biomarkers for prognosis and targets for secondary prevention.

cancer biology↗

bioRxiv2021

Stromal remodeling regulates dendritic cell abundance and activity in the tumor microenvironment

Stimulatory dendritic cells (SDC), enriched within Batf3-DC (cDC1), engage in productive interactions with CD8+ effectors along tumor-stroma boundaries. The paradoxical accumulation of "poised" cross-presenting Batf3-DC within stromal sheets, distal to tumoral nests, is unlikely to simply reflect passive exclusion away from immunosuppressive tumor cores. Drawing parallels with embryonic morphogenesis, we hypothesized that invasive margin stromal remodeling may generate developmentally conserved cell-fate cues that regulate Batf3-DC behavior. We find that CD8+ T-cells massively infiltrate tumor matrices undergoing proteoglycan versican (VCAN) proteolysis, an essential organ-sculpting modification in development and adult tissue-plane forging. VCAN proteolysis releases a bioactive fragment (matrikine), versikine, that is necessary and sufficient for Batf3-DC accumulation. Versikine does not influence tumor-seeding pre-DC differentiation; rather, it orchestrates a distinctive activation program conferring exquisite sensitivity to DNA-sensing, coupled with survival support from atypical innate lymphoid cells. Thus, homeostatic signals from stroma invasion regulate SDC survival and activity to promote T- cell inflammation. HIGHLIGHTSO_LITumor stroma remodeling generates cross-presenting DC survival and activation cues. C_LIO_LIStromal-activated Batf3-DC are hypersensitive to dsDNA-sensing. C_LIO_LIStromal signals promote atypical innate lymphoid cells (GM-CSFhi/ IFN{gamma}lo). C_LIO_LIT-cell repriming by stroma-licensed Batf3-DC may overcome exclusion at tumor margins. C_LI

immunology↗

bioRxiv2021

The breast pre-cancer atlas illustrates the molecular and micro-environmental diversity of ductal carcinoma in situ

Micro-environmental and molecular factors mediating the progression of Breast Ductal Carcinoma In Situ (DCIS) are not well understood, impeding the development of prevention strategies and the safe testing of treatment de-escalation. We addressed methodological barriers and characterized the mutational, transcriptional, histological and microenvironmental landscape across 85 multiple micro-dissected regions from 39 cases. Most somatic alterations, including whole genome duplications, were clonal, but genetic divergence increased with physical distance. Phenotypic and subtype heterogeneity frequently associated with underlying genetic heterogeneity and regions with low-risk features preceded those with high-risk features according to the inferred phylogeny. B- and T-lymphocytes spatial analysis identified 3 immune states, including an epithelial excluded state located preferentially at DCIS regions, and characterized by histological and molecular features of immune escape, independently from molecular subtypes. Such breast pre-cancer atlas with uniquely integrated observations will help scope future expansion studies and build finer models of outcomes and progression risk.

genomics↗

bioRxiv2019

Avant-garde: An automated data-driven DIA data curation tool.

Data-Independent Acquisition (DIA) is a technique that promises to comprehensively detect and quantify all peptides above an instruments limit of detection. Several software tools to analyze DIA data have been developed in recent years. However, several challenges still remain, like confidently identifying peptides, defining integration boundaries, dealing with interference for selected transitions, and scoring and filtering of peptide signals in order to control false discovery rates. In practice, a visual inspection of the signals is still required, which is impractical with large datasets. Avant-garde is a new tool to refine DIA (and PRM) by removing interfered transitions, adjusting integration boundaries and scoring peaks to control the FDR. Unlike other tools where MS runs are scored independently from each other, Avant-garde uses a novel data-driven scoring strategy. DIA signals are refined by learning from the data itself, using all measurements in all samples together to achieve the best optimization. We evaluated the performances of Avant-garde with a calibrated sample using spiked-in standards in a complex background, a phospho-enriched dataset (Abelin et al, 2016), and two complex hybrid proteome samples for benchmarking DIA software tools. The results clearly showed that Avant-garde is capable of improving the selectivity, accuracy, and reproducibility of the quantification results in very complex biological matrices. We have further shown that it can evaluate the suitability of a peak to be used for quantification reaching the same levels of selectivity, accuracy, and reproducibility obtained with manual validation.

bioinformatics↗

bioRxiv2017

A Library of Phosphoproteomic and Chromatin Signatures for Characterizing Cellular Responses to Drug Perturbations

Though the added value of proteomic measurements to gene expression profiling has been demonstrated, profiling of gene expression on its own remains the dominant means of understanding cellular responses to perturbation. Direct protein measurements are typically limited due to issues of cost and scale; however, the recent development of high-throughput, targeted sentinel mass spectrometry assays provides an opportunity for proteomics to contribute at a meaningful scale in high-value areas for drug development. To demonstrate the feasibility of a systematic and comprehensive library of perturbational proteomic signatures, we profiled 90 drugs (in triplicate) in six cell lines using two different proteomic assays -- one measuring global changes of epigenetic marks on histone proteins and another measuring a set of peptides reporting on the phosphoproteome -- for a total of more than 3,400 samples. This effort represents a first-of-its-kind resource for proteomics. The majority of tested drugs generated reproducible responses in both phosphosignaling and chromatin states, but we observed differences in the responses that were cell line-and assay-specific. We formalized the process of comparing response signatures within the data using a concept called connectivity, which enabled us to integrate data across cell types and assays. Furthermore, it facilitated incorporation of transcriptional signatures. Consistent connectivity among cell types revealed cellular responses that transcended cell-specific effects, while consistent connectivity among assays revealed unexpected associations between drugs that were confirmed by experimental follow-up. We further demonstrated how the resource could be leveraged against public domain external datasets to recognize therapeutic hypotheses that are consistent with ongoing clinical trials for the treatment of multiple myeloma and acute lymphocytic leukemia (ALL). These data are available for download via the Gene Expression Omnibus (accession GSE101406), and web apps for interacting with this resource are available at https://clue.io/proteomics.\n\nHighlightsO_LIFirst-of-its-kind public resource of proteomic responses to systematically administered perturbagens\nC_LIO_LIDirect proteomic profiling of phosphosignaling and chromatin states in cells for 90 drugs in six different cell lines\nC_LIO_LIExtends Connectivity Map concept to proteomic data for integration with transcriptional data\nC_LIO_LIEnables recognition of unexpected, cell type-specific activities and potential translational therapeutic opportunities\nC_LI

systems biology↗