Carrasco-Garcia, Estefania; Lopez, Lidia; Moncho-Amor, Veronica; Carazo, Fernando; Aldaz, Paula; Collado, Manuel; Bell, Donald; Gaafar, Ayman; Karamitopoulou, Eva; Tzankov, Alexandar; Hidalgo, Manuel; Rubio, Ángel; Serrano, Manuel; Lawrie, Charles H; Lovell-Badge, Robin; Matheu, Ander (2022). SOX9 Triggers Different Epithelial to Mesenchymal Transition States to Promote Pancreatic Cancer Progression. Cancers, 14(4) MDPI AG 10.3390/cancers14040916
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BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers mainly due to spatial obstacles to complete resection, early metastasis and therapy resistance. The molecular events accompanying PDAC progression remain poorly understood. SOX9 is required for maintaining the pancreatic ductal identity and it is involved in the initiation of pancreatic cancer. In addition, SOX9 is a transcription factor linked to stem cell activity and is commonly overexpressed in solid cancers. It cooperates with Snail/Slug to induce epithelial-mesenchymal transition (EMT) during neural development and in diseases such as organ fibrosis or different types of cancer.
METHODS
We investigated the roles of SOX9 in pancreatic tumor cell plasticity, metastatic dissemination and chemoresistance using pancreatic cancer cell lines as well as mouse embryo fibroblasts. In addition, we characterized the clinical relevance of SOX9 in pancreatic cancer using human biopsies.
RESULTS
Gain- and loss-of-function of SOX9 in PDAC cells revealed that high levels of SOX9 increased migration and invasion, and promoted EMT and metastatic dissemination, whilst SOX9 silencing resulted in metastasis inhibition, along with a phenotypic reversion to epithelial features and loss of stemness potential. In both contexts, EMT factors were not altered. Moreover, high levels of SOX9 promoted resistance to gemcitabine. In contrast, overexpression of SOX9 was sufficient to promote metastatic potential in K-Ras transformed MEFs, triggering EMT associated with Snail/Slug activity. In clinical samples, SOX9 expression was analyzed in 198 PDAC cases by immunohistochemistry and in 53 patient derived xenografts (PDXs). SOX9 was overexpressed in primary adenocarcinomas and particularly in metastases. Notably, SOX9 expression correlated with high vimentin and low E-cadherin expression.
CONCLUSIONS
Our results indicate that SOX9 facilitates PDAC progression and metastasis by triggering stemness and EMT.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Service Sector > Institute of Pathology |
UniBE Contributor: |
Karamitopoulou Diamantis, Evanthia |
Subjects: |
500 Science > 570 Life sciences; biology 600 Technology > 610 Medicine & health |
ISSN: |
2072-6694 |
Publisher: |
MDPI AG |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
01 Mar 2022 14:31 |
Last Modified: |
05 Dec 2022 16:11 |
Publisher DOI: |
10.3390/cancers14040916 |
PubMed ID: |
35205666 |
Uncontrolled Keywords: |
EMT SOX9 chemoresistance metastasis pancreatic cancer plasticity |
BORIS DOI: |
10.48350/166104 |
URI: |
https://boris.unibe.ch/id/eprint/166104 |
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