transcriptomic analysis

Personalized Spatial Regulatory Networks to Decode Breast Cancer Microenvironments

PROJECT SUMMARY Triple-negative breast cancer (TNBC) is an aggressive subtype with early recurrence, high metastatic burden, and limited treatment options. While genomic alterations contribute to its progression, epigenetic plasticity and spatial organization within the tumor microenvironment (TME) play critical roles in intra-tumor heterogeneity, immune evasion, and therapy resistance, yet remain poorly understood. To address this, we will develop a cost- effective and scalable methodology that integrates spatial ATAC-seq, spatial in situ transcriptomics (Xenium), and single-nucleus (sn) Epi Multiome sequencing (snRNA-seq + snATAC-seq) from core-needle biopsies, enabling high-resolution mapping of gene regulatory networks within the intact TME. Our preliminary data from six TNBC biopsies demonstrate that spatial in situ transcriptomics and spatial ATAC-seq provide critical insights into tissue architecture but suffer from data sparsity, necessitating the integration of single-nucleus Epi Multiome data to enhance cell-type annotation and impute missing genomic features. In Aim 1, we will establish a multi- modal workflow that maximizes molecular insights from limited biopsy material by optimizing tissue-preserving and multiplexed sequencing approaches. This includes leveraging patient-specific genetic variation to deconvolute nuclei-derived data and linking it to spatial transcriptomic and spatial chromatin accessibility profiles. In Aim 2, we will develop a computational framework to integrate these multi-layered datasets, enabling spatially resolved epigenomic-transcriptomic analysis that identifies key regulatory chromatin elements and transcriptional programs associated with TNBC progression, immune infiltration, and therapy resistance. This project will generate the first comprehensive, patient-specific spatial regulatory atlas of TNBC, providing fundamental insights into how chromatin accessibility and gene expression interact within the TME. Ultimately, this work will pave the way for novel precision oncology strategies, biomarker discovery, and the development of targeted therapies that address TNBC’s spatial and molecular heterogeneity.

Sparks, flames, and inferno: epileptogenesis in the glioblastoma microenvironment

Glioblastoma cells trigger pharmacoresistant seizures that may promote tumor growth and diminish the quality of remaining life. To define the relationship between growth of glial tumors and their neuronal microenvironment, and to identify genomic biomarkers and mechanisms that may point to better prognosis and treatment of drug resistant epilepsy in brain cancer, we are analyzing a new generation of genetically defined CRISPR/in utero electroporation inborn glioblastoma (GBM) tumor models engineered in mice. The molecular pathophysiology of glioblastoma cells and surrounding neurons and untransformed astrocytes are compared at serial stages of tumor development. Initial studies reveal that epileptiform EEG spiking is a very early and reliable preclinical signature of GBM expansion in these mice, followed by rapidly progressive seizures and death within weeks. FACS-sorted transcriptomic analysis of cortical astrocytes reveals the expansion of a subgroup enriched in pro-synaptogenic genes that may drive hyperexcitability, a novel mechanism of epileptogenesis. Using a prototypical GBM IUE model, we systematically define and correlate the earliest appearance of cortical hyperexcitability with progressive cortical tumor cell invasion, including spontaneous episodes of spreading cortical depolarization, innate inflammation, and xCT upregulation in the peritumoral microenvironment. Blocking this glutamate exporter reduces seizure load. We show that the host genome contributes to seizure risk by generating tumors in a monogenic deletion strain (MapT/tau -/-) that raises cortical seizure threshold. We also show that the tumor variant profile determines epilepsy risk. Our genetic dissection approach sets the stage to broadly explore the developmental biology of personalized tumor/host interactions in mice engineered with novel human tumor mutations in specified glial cell lineages.

Functional and transcriptomic analysis of induced pluripotent stem cell microglia in Huntington’s Disease

Spot-on! Spatial transcriptomic analysis of L-DOPA-induced gene expression in a mouse model of parkinsonism

Transcriptomic analysis’ of axon regeneration-inducing manipulations discover distinct molecular programs defining a cell’s fate to die, survive or regenerate after an injury

Transcriptomic analysis of cytoplasmic polyadenylation element binding proteins (CPEBs) in Schizophrenia

Transcriptomic analysis of hippocampal subregions after induction of acute seizures by electric stimulation of the perforant pathway in rats

Proteomic and transcriptomic analysis of Id2- and Ascl4-induced wiring in adult hippocampal granule cells

FENS Forum 2024

Transcriptomic analysis of the effects of a single dose of ibogaine: Uncovering potential therapeutic pathways in mice

FENS Forum 2024

Visual impairments in a mouse model of multiple sclerosis: A transcriptomic analysis

FENS Forum 2024