Publicação
Exploring the crosstalk between Sialyl-Tn (STn) expression and Pancreatic ductal adenocarcinoma (PDAC) progression
| Resumo: | Pancreatic cancer (PC) is the sixth leading cause of cancer-related deaths due to the lack of effective treatment and its intrinsic aggressiveness. Pancreatic ductal adenocarcinoma (PDAC) represents 85-90% of PC cases, and these tumors are normally detected in advanced stages further contributing to the high mortality of these cancers. In pancreas carcinogenesis, there are three well-known PDAC precursors: Pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN). Glycosylation is a post-translational modification crucial to many biological processes, which become aberrant in neoplastic cells, allowing them to take over many hallmarks of cancer. Particularly, aberrant sialylation results in the formation of cancer specific glycans, including truncated O-GalNAc glycans. Sialyl-Tn (STn) is one of these truncated O-GalNAc glycans being expressed in more than 80% of human epithelial cancers, including PDAC, and nearly absent in healthy tissues. STn expression is mainly attributed to the overexpression of ST6GalNAc I sialyltransferase being commonly associated with poor prognosis contributing to cancer progression and invasion. However, STn profile in a meaningful cohort in different PDAC development stages and its impact on survival in cancer remains yet to be clarified. Therefore, in this work, we evaluated the STn expression during PDAC progression in a meaningful cohort of patients. Additionally, we validated an in vitro model of PDAC that overexpresses STn to enable future experiments on this topic, and finally we revised information on the survival impact of STn in different cancer types. To accomplished this, we examined 185 tissue samples from patients by immunohistochemistry, where we identified variable STn expression across the different PDAC development stages while absent in normal pancreas. Despite heterogeneity, STn mainly occurs in later events of PDAC development, and seems to have a role in PDAC progression. Additionally, we also evaluated if neoadjuvant chemotherapy would have any impact on STn expression, but no significant correlation was observed. Then, the in vitro model was validated, by analyzing PANC-1 cells overexpressing or not ST6GalNAc I by western blot and flow cytometry. We observed that cells overexpressing ST6GalNAc I showed STn expression unlike the ones not overexpressing ST6GalNAc I, validating the model and confirming the role of this enzyme in STn expression. Finally, we performed a literature search on the survival impact of STn and identified that STn+ cases tend to have worse outcomes, yet the impact of STn varies between the different cancer types. Interestingly, no PDAC cohort was found, highlighting the need to assess the survival impact of STn in these patients. |
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| Autores principais: | Soares, Ana Carolina Frade |
| Assunto: | Pancreatic ductal adenocarcinoma PDAC precursor lesions sialyl-Tn immunohistochemistry survival |
| Ano: | 2024 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade Nova de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório Institucional da UNL |
| Resumo: | Pancreatic cancer (PC) is the sixth leading cause of cancer-related deaths due to the lack of effective treatment and its intrinsic aggressiveness. Pancreatic ductal adenocarcinoma (PDAC) represents 85-90% of PC cases, and these tumors are normally detected in advanced stages further contributing to the high mortality of these cancers. In pancreas carcinogenesis, there are three well-known PDAC precursors: Pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN). Glycosylation is a post-translational modification crucial to many biological processes, which become aberrant in neoplastic cells, allowing them to take over many hallmarks of cancer. Particularly, aberrant sialylation results in the formation of cancer specific glycans, including truncated O-GalNAc glycans. Sialyl-Tn (STn) is one of these truncated O-GalNAc glycans being expressed in more than 80% of human epithelial cancers, including PDAC, and nearly absent in healthy tissues. STn expression is mainly attributed to the overexpression of ST6GalNAc I sialyltransferase being commonly associated with poor prognosis contributing to cancer progression and invasion. However, STn profile in a meaningful cohort in different PDAC development stages and its impact on survival in cancer remains yet to be clarified. Therefore, in this work, we evaluated the STn expression during PDAC progression in a meaningful cohort of patients. Additionally, we validated an in vitro model of PDAC that overexpresses STn to enable future experiments on this topic, and finally we revised information on the survival impact of STn in different cancer types. To accomplished this, we examined 185 tissue samples from patients by immunohistochemistry, where we identified variable STn expression across the different PDAC development stages while absent in normal pancreas. Despite heterogeneity, STn mainly occurs in later events of PDAC development, and seems to have a role in PDAC progression. Additionally, we also evaluated if neoadjuvant chemotherapy would have any impact on STn expression, but no significant correlation was observed. Then, the in vitro model was validated, by analyzing PANC-1 cells overexpressing or not ST6GalNAc I by western blot and flow cytometry. We observed that cells overexpressing ST6GalNAc I showed STn expression unlike the ones not overexpressing ST6GalNAc I, validating the model and confirming the role of this enzyme in STn expression. Finally, we performed a literature search on the survival impact of STn and identified that STn+ cases tend to have worse outcomes, yet the impact of STn varies between the different cancer types. Interestingly, no PDAC cohort was found, highlighting the need to assess the survival impact of STn in these patients. |
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