SOX9 Triggers Different Epithelial to Mesenchymal Transition States to Promote Pancreatic Cancer Progression.

Estefania Carrasco-Garcia,Ángel Rubio,Robin Lovell-Badge,Manuel Serrano,Paula Aldaz,Charles H Lawrie,Manuel Hidalgo,Fernando Carazo,Ander Matheu,Veronica Moncho-Amor,Manuel Collado,Ayman Gaafar,Eva Karamitopoulou,Alexandar Tzankov,Lidia Lopez,Donald Bell

doi:10.3390/cancers14040916

Abstract

Simple SummaryPancreatic cancers are lethal types of cancer. A majority of patients progress to an advanced and metastatic disease, which remains a major clinical problem. Therefore, it is crucial to identify critical regulators to help predict the disease progression and to develop more efficacious therapeutic approaches. In this work we found that an increased expression of the developmental factor SOX9 is associated with metastasis, a poor prognosis and resistance to therapy in pancreatic ductal adenocarcinoma patients and in cell cultures. We also found that this effect is at least in part due to the ability of SOX9 to regulate the activity of stem cell factors, such as BMI1, in addition to those involved in EMT and metastasis. 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.

Highlights

Metastasis is a complex process by which cancer cells spread from the primary tumor and colonize distant tissues in the body
The progressive growth of these cells was traced in vivo and was detected in mice injected with Z/Sox9tg cells, but not in those injected with wt mouse embryo fibroblasts (MEFs) (Figure 1A)
As cancer cell motility and invasion into the basement membrane are associated with the induction of epithelial-mesenchymal transition (EMT) and metastasis [6], we investigated these capabilities in pancreatic cancer cells overexpressing SOX9

Summary

Introduction

Metastasis is a complex process by which cancer cells spread from the primary tumor and colonize distant tissues in the body. The EMT process may have other important implications for cancer cells such as the acquisition of stem cell-like properties [6–8], which are closely implicated in therapy resistance [9]. This is not always associated with EMT processes in the context of metastasis [1,10]. 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. 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

Results

Discussion

Conclusion