Biology subjects

Byers, L.

Publications and source records attributed to Byers, L..

5 recordsLinked to original sources

bioRxiv2025

CyTOF-based profiling of circulating tumor cells predicts aggressiveness and therapy response in SCLC liquid biopsies at a personalized level

Small-cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma characterized by high numbers of circulating tumor cells (CTCs). We applied CyTOF and a 20-marker antibody panel to detect and phenotype CTCs directly in liquid biopsies of 51 SCLC patients (treatment-naive, chemotherapy and immunotherapy-treated, and tarlatamab-treated), of which a subset were longitudinally tracked. Unsupervised clustering revealed distinct cell populations enriched in patient liquid biopsies compared to those from healthy donors. Further analysis identified CTC populations of the three established SCLC subtypes driven by the high expression of ASCL1, NeuroD1, and POU2F3 transcription factors respectively. Significant differences in CTC EMT markers, established therapeutic targets (e.g. DLL3), and subtype heterogeneity were observed between naive versus treated samples. Changes in subtype proportions were observed in longitudinally tracked samples in both treatment modalities. Our study demonstrates the utility of CyTOF for high-resolution CTC profiling, offering dynamic insights into CTC heterogeneity, treatment response, and resistance mechanisms. HighlightsO_LICTCs can be detected, subtyped and phenotyped in SCLC liquid biopsies using CyTOF C_LIO_LICTC subtypes and EMT states are differentially associated with treatment modality C_LIO_LICTC DLL3 levels and epithelial features increase following anti-DLL3 BiTE therapy C_LIO_LICyTOF CTC subtyping can predict disease aggressiveness C_LIO_LILongitudinal tracking reveals CTC plasticity and therapy response correlations C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/694669v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@384cbcorg.highwire.dtl.DTLVardef@35dd37org.highwire.dtl.DTLVardef@4e7d61org.highwire.dtl.DTLVardef@1098e4f_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Scalable 3D Bioprinting of Human Islets in a Pancreatic Decellularized Extracellular Matrix-Enriched Bioink for Beta-Cell Replacement Therapy

Allogeneic cell transplantation such as beta-cell replacement for treatment of type 1 diabetes (T1D) is constrained by poor graft survival and functionality, immune rejection, and the lack of scalable biomanufacturing processes. Here, we engineered functional human islet constructs that replicate the physiomimetic human pancreatic microenvironment by employing a clinically-scalable 3D bioprinting system. To support human islet viability and function, we developed alginate-based bioinks incorporating human pancreatic decellularized extracellular matrix (dECM). These bioink formulations were optimized for shear-thinning properties for extrusion of human islets, as well as selective permeability that supports nutrient and therapeutic molecule exchange. Extrusion-based printing parameters were refined to minimize shear stress-induced damage to human islets. The resulting bioprinted pancreatic constructs demonstrated robust structural integrity, high human islet viability (>85%), and long-term glucose-stimulated insulin secretion (GSIS) over a 21-days in vitro culture period, even at a high islet packing density (10,000 islet equivalent/mL) while free islet controls displayed a significant functional decline. The higher performance of bioprinted islets maybe attributable to the supportive 3D dECM-rich microenvironment mitigating culture-induced stress by recapitulating the islet pancreatic niche. This scalable 3D dECM-alginate bioprinted platform represents a new advanced functional material for advancing clinically translatable bio-artificial pancreas therapies for T1D.

bioengineering↗

bioRxiv2020

Resolving the spatial and cellular architecture of lung adenocarcinoma by multi-region single-cell sequencing

Little is known of the geospatial architecture of individual cell populations in lung adenocarcinoma (LUAD) evolution. Here, we perform single-cell RNA sequencing of 186,916 cells from 5 early-stage LUADs and 14 multi-region normal lung tissues of defined spatial proximities from the tumors. We show that cellular lineages, states, and transcriptomic features geospatially evolve across normal regions to LUADs. LUADs also exhibit pronounced intratumor cell heterogeneity within single sites and transcriptional lineage-plasticity programs. T regulatory cell phenotypes are increased in normal tissues with proximity to LUAD, in contrast to diminished signatures and fractions of cytotoxic CD8+ T cells, antigen-presenting macrophages and inflammatory dendritic cells. We further find that the LUAD ligand-receptor interactome harbors increased expression of epithelial CD24 which mediates pro-tumor phenotypes. These data provide a spatial atlas of LUAD evolution, and a resource for identification of targets for its treatment. Statement of significanceThe geospatial ecosystem of the peripheral lung and early-stage LUAD is not known. Our multi-region single-cell sequencing analyses unravel cell populations, states, and phenotypes in the spatial and ecological evolution of LUAD from the lung that comprise high-potential targets for early interception.

cancer biology↗

bioRxiv2020

Genomic and TCR Repertoire Intratumor Heterogeneity of Small-cell Lung Cancer and its Impact on Survival

Small-cell lung cancer (SCLC) is speculated to harbor complex genomic intratumor heterogeneity (ITH) associated with high recurrence rate and suboptimal response to immunotherapy. Here, we revealed a rather homogeneous mutational landscape but extremely suppressed and heterogeneous T cell receptor (TCR) repertoire in SCLCs. Higher mutational burden, lower chromosomal copy number aberration (CNA) burden, less CNA ITH and less TCR ITH were associated with longer overall survival of SCLC patients. Compared to non-small cell lung cancers (NSCLCs), SCLCs had similar predicted neoantigen burden and mutational ITH, but significantly more suppressed and heterogeneous TCR repertoire that may be associated with higher CNA burden and CNA ITH in SCLC. Novel therapeutic strategies targeting CNA could potentially improve the tumor immune microenvironment and response to immunotherapy in SCLC.

genomics↗

bioRxiv2020

Single-cell analysis of human lung epithelia reveals concomitant expression of the SARS-CoV-2 receptor ACE2 with multiple virus receptors and scavengers in alveolar type II cells

The novel coronavirus SARS-CoV-2 was identified as the causative agent of the ongoing pandemic COVID 19. COVID-19-associated deaths are mainly attributed to severe pneumonia and respiratory failure. Recent work demonstrated that SARS-CoV-2 binds to angiotensin converting enzyme 2 (ACE2) in the lung. To better understand ACE2 abundance and expression patterns in the lung we interrogated our in-house single-cell RNA-sequencing dataset containing 70,085 EPCAM+ lung epithelial cells from paired normal and lung adenocarcinoma tissues. Transcriptomic analysis revealed a diverse repertoire of airway lineages that included alveolar type I and II, bronchioalveolar, club/secretory, quiescent and proliferating basal, ciliated and malignant cells as well as rare populations such as ionocytes. While the fraction of lung epithelial cells expressing ACE2 was low (1.7% overall), alveolar type II (AT2, 2.2% ACE2+) cells exhibited highest levels of ACE2 expression among all cell subsets. Further analysis of the AT2 compartment (n = 27,235 cells) revealed a number of genes co-expressed with ACE2 that are important for lung pathobiology including those associated with chronic obstructive pulmonary disease (COPD; HHIP), pneumonia and infection (FGG and C4BPA) as well as malarial/bacterial (CD36) and viral (DMBT1) scavenging which, for the most part, were increased in smoker versus light or non-smoker cells. Notably, DMBT1 was highly expressed in AT2 cells relative to other lung epithelial subsets and its expression positively correlated with ACE2. We describe a population of ACE2-positive AT2 cells that co-express pathogen (including viral) receptors (e.g. DMBT1) with crucial roles in host defense thus comprising plausible phenotypic targets for treatment of COVID-19.

genomics↗