Biology subjects

Spitzer, A.

Publications and source records attributed to Spitzer, A..

4 recordsLinked to original sources

bioRxiv2025

Spatial and Single-cell Transcriptomics Reveal Programs Governing Fibroblastic Foci Fibroblasts

RationaleFibroblastic foci (FF) are central for fibrosis propagation in idiopathic pulmonary fibrosis (IPF), yet their resident fibroblast subpopulation remains poorly defined. ObjectiveTo deeply characterize FF-fibroblasts and identify programs governing their differentiation and activation. MethodsGeoMx spatial transcriptomics was applied to IPF lung regions, comparing carefully delineated FF (excluding overlying epithelium) with areas of established fibrosis, to derive an FF-specific signature. This signature was projected onto a large single-cell RNA-sequencing (scRNA-seq) dataset to identify an FF-specific fibroblast cluster, facilitating its deep characterization. Measurements and Main ResultsGeoMx revealed 272 increased genes in FF; this FF-signature was validated against several independent spatial transcriptomics and proteomics datasets. FF-signature genes were highly enriched in a specific cluster of fibroblasts in the IPF scRNA-seq dataset. MMP11 was the most specific gene of the FF-fibroblast cluster, and was validated using in situ RNA hybridization. Furthermore, higher MMP11 bronchoalveolar lavage protein levels were found in progressive pulmonary fibrosis and were associated with worse outcome in Cox regression (HR 4.54, 95% CI 1.24-15.8). Cell-cell interaction analysis with fibroblasts and adjacent aberrant basaloid cells, detected signals that may induce the FF-fibroblast signature, including from TGF-{beta} superfamily ligands. Using trajectory and transcription factor (TF) analysis we show that the trajectory from non-FF to FF-specific fibroblasts is correlated with activation of EMT-associated TFs and deactivation of AP-1 family TFs. ConclusionsWe identified transcriptional programs governing FF-fibroblasts, for which MMP11 serves as a novel highly-specific biomarker with prognostic significance. We highlight potential regulators whose targeting may curb pulmonary fibrosis progression.

genomics↗

bioRxiv2024

Subtypes and proliferation patterns of small intestine neuroendocrine tumors revealed by single cell RNA sequencing

Neuroendocrine tumors (NETs) occur primarily in the small intestine, lung and pancreas. Due to their rarity compared to other malignancies in these organs, their complex biology remains poorly understood, including their oncogenesis, tumor composition and the intriguing phenomena of mixed neuroendocrine non-neuroendocrine neoplasms (MiNEN). Here we profiled ten low-grade small intestine NET (SiNET) samples as well as one mixed lung tumor by single-cell or single-nuclei RNA-seq. We find that SiNETs are largely separated into two distinct subtypes, in which the neuroendocrine cells upregulate epithelial or neuronal markers, respectively. Surprisingly, in both subtypes the neuroendocrine cells are largely non-proliferative while higher proliferation is observed in multiple non-malignant cell types. Specifically, B and plasma cells are highly proliferative in the epithelial-like SiNET subtype, potentially reflecting the outcome of high Migration Inhibitory Factor (MIF) expression in those tumors, which may constitute a relevant target. Finally, our analysis of a mixed lung neuroendocrine tumor identifies a population of putative progenitor cells that may give rise to both neuroendocrine and non-neuroendocrine (squamous) cells, potentially explaining the origin of the mixed histology. Taken together, our results provide important insights and hypotheses regarding the biology of neuroendocrine neoplasms.

cancer biology↗

bioRxiv2021

The transcriptional hallmarks of intra-tumor heterogeneity across a thousand tumors

Each tumor contains malignant cells that differ in genotype, phenotype, and in their interactions with the tumor micro-environment (TME). This results in distinct integrated cellular states that govern intra-tumor heterogeneity (ITH), a central challenge of cancer therapeutics. Dozens of recent studies have begun to describe ITH by single cell RNA-seq, but each study typically profiledonly a small number of tumors and provided a narrow view of transcriptional ITH. Here, we curate, annotate and integrate the data from 77 different studies to reveal the patterns of ITH across 1,163 tumor samples covering 24 tumor types. Focusing on the malignant cells, we find thousands of transcriptional ITH programs that can be described by 41 consensus meta-programs (MPs), each consisting of dozens of genes that are coordinately upregulated in subpopulations of cells within many different tumors. The MPs cover diverse cellular processes and differ in their cancer-type distribution. General MPs associated with processes such as cell cycle and stress vary within most tumors, while context-specific MPs reflect the unique biology of particular cancer types, often resembling developmental cell types and suggesting the co-existence of variable differentiation states within tumors. Some of the MPs are further associated with overall tumor proliferation or immune state, highlighting their potential clinical significance. Based on functional similarities among MPs, we propose a set of 11 hallmarks that together account for the majority of observed ITH programs. Given the breadth and scope of the investigated cohort, the MPs and hallmarks described here reflect the first comprehensive pan-cancer description of transcriptional ITH.

cancer biology↗

bioRxiv2020

Searching for biological feedstock material: 3D printing of wood particles from house borer and drywood termite frass

Frass (fine powdery refuse or fragile perforated wood produced by the activity of boring insects) of larvae of the European house borer and of drywood termites was tested as a natural and novel feedstock for 3D-printing of wood-based materials. Small particles produced by the drywood termite Incisitermes marginipennis and the European house borer (EHB) Hylotrupes bajulus during feeding in construction timber, were used. Frass is a powdery material of particularly consistent quality that is essentially biologically processed wood mixed with debris of wood and faeces. The filigree-like particles flow easily permitting the build-up of wood-based structures in a layer wise fashion using the Binder Jetting printing process. The quality of powders produced by different insect species was compared along with the processing steps and properties of the printed parts. Drywood termite frass with a HR = 1.1 with {rho}Bulk = 0.67 g.cm-3 and {rho}Tap = 0.74 g.cm-3 was perfectly suited to deposition of uniformly packed layers in 3D printing. We suggest that a variety of naturally available feedstocks could be used in environmentally responsible approaches to scientific material sciences/additive manufacturing.

bioengineering↗