Biology subjects

Hennessey, C.

Publications and source records attributed to Hennessey, C..

3 recordsLinked to original sources

bioRxiv2025

GLIS3 Marks a Neural-like Progenitor Cell State that Drives Metastasis in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) has a high rate of recurrence and metastasis despite intensive therapy. The neural-like progenitor (NRP) transcriptional program is enriched in residual disease after neoadjuvant chemotherapy and radiotherapy; however, the mechanisms for increased NRP expression in the post-treatment setting remain unclear. Here, we find that NRP signatures are strongly enriched in tissue injury and regeneration, and NRP cancer cells co-express transcription factors involved in pancreatic development. We identify both cell autonomous and ligand mediated mechanisms for inducing NRP expression in vitro. We establish and characterize isogenic mouse organoid overexpression models for transcription factors associated with the NRP, classical, and basal-like states. We discovered that Glis3 is a key NRP-associated transcription factor that drives malignant properties including greater clonogenicity, tumor growth, and metastasis compared to isogenic models for the classical and basal-like states. Our work highlights the emergence of clinically relevant developmental regeneration programs in the post-treatment context.

cancer biology↗

bioRxiv2024

Cell states and neighborhoods in distinct clinical stages of primary and metastatic esophageal adenocarcinoma

Esophageal adenocarcinoma (EAC) is a highly lethal cancer of the upper gastrointestinal tract with rising incidence in western populations. To decipher EAC disease progression and therapeutic response, we performed multiomic analyses of a cohort of primary and metastatic EAC tumors, incorporating single-nuclei transcriptomic and chromatin accessibility sequencing, along with spatial profiling. We identified tumor microenvironmental features previously described to associate with therapy response. We identified five malignant cell programs, including undifferentiated, intermediate, differentiated, epithelial-to-mesenchymal transition, and cycling programs, which were associated with differential epigenetic plasticity and clinical outcomes, and for which we inferred candidate transcription factor regulons. Furthermore, we revealed diverse spatial localizations of malignant cells expressing their associated transcriptional programs and predicted their significant interactions with microenvironmental cell types. We validated our findings in three external single-cell RNA-seq and three bulk RNA-seq studies. Altogether, our findings advance the understanding of EAC heterogeneity, disease progression, and therapeutic response.

cancer biology↗

bioRxiv2020

Neonatal enteropathogenic Escherichia coli infection disrupts microbiota-gut-brain axis signaling

BackgroundDiarrheal diseases are a leading cause of death in children under age five worldwide. Repeated early life exposures to diarrheal pathogens can result in co-morbidities including stunted growth and cognitive deficits suggesting an impairment in the microbiota-gut-brain (MGB) axis. MethodsNeonatal C57BL/6 mice were infected with EPEC (strain e2348/69; {Delta}escV [T3SS mutant]), or vehicle (LB broth) via orogastric gavage (105 CFU) at post-natal day (P7). Behavior (novel object recognition [NOR] task, light/dark [L/D] box, and open field test [OFT]), intestinal physiology (Ussing chambers), and the microbiota (16S Illumina sequencing) were assessed in adulthood (6-8 weeks). ResultsNeonatal infection of mice with EPEC impaired recognition memory (NOR task), coupled with increased neurogenesis (Ki67 and doublecortin immunostaining) and neuroinflammation (increased microglia activation [Iba1]) in adulthood. Intestinal pathophysiology was characterized by increased secretory state (short circuit current; Isc) and permeability (conductance; FITC-dextran flux) in the ileum and colon of neonatally EPEC-infected mice, along with increased expression of pro-inflammatory cytokines (Tnf, Il12, Il6) and pattern recognition receptors (Nlr, Tlr). Finally, neonatal EPEC infection caused significant dysbiosis of the gut microbiota, including decreased Firmicutes, in adulthood. ConclusionsTogether these findings demonstrate that infection in early life can significantly impair the MGB axis in adulthood.

microbiology↗