Smythies, L. E. | bioRxiv Science

bioRxiv2023

Novel Biomarkers and Distinct Transcriptomic Profile of Barrett's Esophagus Epithelial Stem Cells

Barretts esophagus, a metaplastic condition that originates in the distal esophagus, is the only known precursor lesion for the development of esophageal adenocarcinoma, which has a devasting 5-year survival rate of <20%. The large number of subjects diagnosed with Barretts esophagus, and therefore at higher risk for esophageal adenocarcinoma, underscores the necessity for biomarkers that would benefit surveillance and potentially early treatment. To address this, we generated epithelial stem cell organoids from normal gastric cardia, non-dysplastic and dysplastic Barretts esophagus, and esophageal and gastric adenocarcinoma. Interestingly, non-dysplastic and dysplastic Barretts esophagus displayed higher expression of multiple archetypical cancer-associated genes compared with both esophageal and gastric adenocarcinoma in addition to expression of the novel biomarker CT83. ST6GAL1, a Golgi sialyltransferase upregulated in multiple epithelioid cancers, was strongly upregulated in dysplastic Barretts esophagus at both mRNA and protein levels. ST6GAL1 protein also was highly expressed in esophageal adenocarcinoma, suggesting that regulation of ST6GAL1 may play a role in Barretts esophagus progression to esophageal adenocarcinoma and serve as a potential biomarker of the development of esophageal cancer.

cancer biology↗

bioRxiv2022

ST6GAL1 sialyltransferase promotes acinar to ductal metaplasia and pancreatic cancer progression

The role of aberrant glycosylation in pancreatic ductal adenocarcinoma (PDAC) remains an under-investigated area of research. In this study, we determined that the ST6GAL1 sialyltransferase, which adds 2,6-linked sialic acids to N-glycosylated proteins, is upregulated in patients with early-stage PDAC, and further increased in advanced disease. A tumor-promoting function for ST6GAL1 was elucidated using tumor xenograft models with human PDAC cells. Additionally, we developed a genetically-engineered mouse (GEM) with transgenic expression of ST6GAL1 in the pancreas, and found that mice with dual expression of ST6GAL1 and oncogenic KRASG12D have greatly accelerated PDAC progression and mortality compared with mice expressing KRASG12D alone. As ST6GAL1 imparts progenitor-like characteristics, we interrogated ST6GAL1s role in acinar to ductal metaplasia (ADM), a process that fosters neoplasia by reprogramming acinar cells into ductal, progenitor-like cells. We confirmed that ST6GAL1 promotes ADM using multiple models including the 266-6 cell line, GEM-derived organoids and tissues, and an in vivo model of inflammation-induced ADM. EGFR is a key driver of ADM and is known to be activated by ST6GAL1-mediated sialylation. Importantly, EGFR activation was dramatically increased in acinar cells and organoids from mice with transgenic ST6GAL1 expression. These collective results highlight a novel glycosylation-dependent mechanism involved in early stages of pancreatic neoplasia.

cancer biology↗