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Cholangiocarcinoma (CCA) is a highly aggressive and metastatic type of malignant carcinoma that is associated with high mortality rates and is difficult to detect at early stages. Core 3 structure is a mucin-type O-glycans synthesized by β1,3-N-acetylglucosaminyltransferase 6 (core 3 synthase), which plays an important role in the digestive system, in particular gastrointestinal goblet cells. It has been reported that core 3 synthase-expressing cells show lower migratory and invasive rates, and lower metastatic activity. A immunohistochemical study also showed that this enzyme was expressed in normal epithelial cells of the colon, but completely disappeared in colorectal cancer cells. The present study aimed to identify biomarkers that could be used to predict the prognosis of patients with CCA. Pathological specimens of 185 CCA tissues were immunohistochemically stained with two antibodies, G8-144 and MECA-79, which recognize core 3 synthase and 6-sulfated N-acetyllactosamine on the extended core-1 O-glycans, respectively. The association between G8-144 or MECA-79 positivity and patient prognosis was statistically analyzed. Positive expression of G8-144 was associated with improved prognosis in patients with distal CCA (dCCA). Patients with dCCA positive for G8-144 showed lower mortality rates than those with negative expression. However, the positive expression of MECA-79 was associated with CCA progression and metastasis, indicating that it is a poor prognostic marker for CCA. In conclusion, as both antibodies resulted in mirror-image staining, the involvement of G8-144 and MECA-79 in O-glycan synthesis could be considered as potential favorable and unfavorable biomarkers, respectively, for CCA prognosis.
The cellular processes that govern tumor resistance to immunotherapy remain poorly understood. To gain insight into these processes, here we perform a genome-scale CRISPR activation screen for genes that enable human melanoma cells to evade cytotoxic T cell killing. Overexpression of four top candidate genes (CD274 (PD-L1), MCL1, JUNB, and B3GNT2) conferred resistance in diverse cancer cell types and mouse xenografts. By investigating the resistance mechanisms, we find that MCL1 and JUNB modulate the mitochondrial apoptosis pathway. JUNB encodes a transcription factor that downregulates FasL and TRAIL receptors, upregulates the MCL1 relative BCL2A1, and activates the NF-κB pathway. B3GNT2 encodes a poly-N-acetyllactosamine synthase that targets >10 ligands and receptors to disrupt interactions between tumor and T cells and reduce T cell activation. Inhibition of candidate genes sensitized tumor models to T cell cytotoxicity. Our results demonstrate that systematic gain-of-function screening can elucidate resistance pathways and identify potential targets for cancer immunotherapy.
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States. Glycans, such as carbohydrate antigen 19-9, are biomarkers of PDAC and are emerging as important modulators of cancer phenotypes. Herein, we used a systems-based approach integrating glycomic analysis of the well-established KC mouse, which models early events in transformation, and analysis of samples from human pancreatic cancer patients to identify glycans with potential roles in cancer formation. We observed both common and distinct patterns of glycosylation in pancreatic cancer across species. Common alterations included increased levels of α-2,3-sialic acid and α-2,6-sialic acid, bisecting GlcNAc and poly-N-acetyllactosamine. However, core fucose, which was increased in human PDAC, was not seen in the mouse, indicating that not all human glycomic changes are observed in the KC mouse model. In silico analysis of bulk and single-cell sequencing data identified ST6 beta-galactoside alpha-2,6-sialyltransferase 1, which underlies α-2,6-sialic acid, as overexpressed in human PDAC, concordant with histological data showing higher levels of this enzyme at the earliest stages. To test whether ST6 beta-galactoside alpha-2,6-sialyltransferase 1 promotes pancreatic cancer, we created a novel mouse in which a pancreas-specific genetic deletion of this enzyme overlays the KC mouse model. The analysis of our new model showed delayed cancer formation and a significant reduction in fibrosis. Our results highlight the importance of a strategic systems approach to identifying glycans whose functions can be modeled in mouse, a crucial step in the development of therapeutics targeting glycosylation in pancreatic cancer.
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