Glucose-Dependent FOXM1 Promotes Epithelial-to-Mesenchymal Transition Via Cellular Metabolism and Targeting Snail in Human Pancreatic Cancer

Tumor cells undergo epithelial-to-mesenchymal transition (EMT) to convert from a benign to a malignant phenotype. Our recent focus has been signaling pathways that promote EMT in response to collagen. We have shown that human pancreatic cancer cells respond to collagen by up-regulating N-cadherin, which promotes tumor growth, invasion, and metastasis. Initial characterization showed that knocking down c-Jun NH2-terminal kinase prevented N-cadherin up-regulation and limited tumor growth and invasion in a mouse model for pancreatic cancer. The current study was designed to understand the pathway from collagen to N-cadherin up-regulation. Initiation of the signal requires two collagen receptors, α2β1 integrin and discoidin domain receptor (DDR) 1. Each receptor propagates signals through separate pathways that converge to up-regulate N-cadherin. Focal adhesion kinase (FAK)–related protein tyrosine kinase (Pyk2) is downstream of DDR1, whereas FAK is downstream of α2β1 integrin. Both receptor complexes rely on the p130 Crk-associated substrate scaffold. Interestingly, Rap1, but not Rho family guanosine triphosphatases, is required for the response to collagen I.

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The Low Chamber Pancreatic Cancer Cells Had Stem-Like Characteristics in Modified Transwell System: Is It a Novel Method to Identify and Enrich Cancer Stem-Like Cells?

BioMed Research International ◽

10.1155/2014/760303 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 3

Author(s):

Dongqing Wang ◽

Haitao Zhu ◽

Yanfang Liu ◽

Qing Liu ◽

Xiaodong Xie ◽

...

Keyword(s):

Pancreatic Cancer ◽

Stem Cell ◽

Epithelial To Mesenchymal Transition ◽

Human Pancreatic Cancer ◽

Stem Cell Markers ◽

Mesenchymal Transition ◽

Pancreatic Cancer Cells ◽

Transwell System

Cancer stem cells (CSCs) or cancer-initiating cells (CICs) play an important role in tumor initiation, progression, metastasis, chemoresistance, and recurrence. It is important to construct an effective method to identify and isolate CSCs for biotherapy of cancer. During the past years, many researchers had paid more attention to it; however, this method was still on seeking. Therefore, compared to the former methods that were used to isolate the cancer stem cell, in the present study, we tried to use modified transwell system to isolate and enrich CSCs from human pancreatic cancer cell lines (Panc-1). Our results clearly showed that the lower chamber cells in modified transwell system were easily forming spheres; furthermore, these spheres expressed high levels of stem cell markers (CD133/CD44/CD24/Oct-4/ESA) and exhibited chemoresistance, underwent epithelial-to-mesenchymal transition (EMT), and possessed the properties of self-renewalin vitroand tumorigenicityin vivo. Therefore, we speculated that modified transwell assay system, as a rapid and effective method, can be used to isolate and enrich CSCs.

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SUV420H2 is an epigenetic regulator of epithelial/mesenchymal states in pancreatic cancer

The Journal of Cell Biology ◽

10.1083/jcb.201705031 ◽

2017 ◽

Vol 217 (2) ◽

pp. 763-777 ◽

Cited By ~ 12

Author(s):

Manuel Viotti ◽

Catherine Wilson ◽

Mark McCleland ◽

Hartmut Koeppen ◽

Benjamin Haley ◽

...

Keyword(s):

Pancreatic Cancer ◽

Large Scale ◽

Epithelial To Mesenchymal Transition ◽

Human Pancreatic Cancer ◽

State Control ◽

Mesenchymal Transition ◽

Mesenchymal To Epithelial Transition ◽

Repressive Mark ◽

Epigenetic Regulator ◽

Identity Shifts

Epithelial-to-mesenchymal transition is implicated in metastasis, where carcinoma cells lose sessile epithelial traits and acquire mesenchymal migratory potential. The mesenchymal state is also associated with cancer stem cells and resistance to chemotherapy. It might therefore be therapeutically beneficial to promote epithelial identity in cancer. Because large-scale cell identity shifts are often orchestrated on an epigenetic level, we screened for candidate epigenetic factors and identified the histone methyltransferase SUV420H2 (KMT5C) as favoring the mesenchymal identity in pancreatic cancer cell lines. Through its repressive mark H4K20me3, SUV420H2 silences several key drivers of the epithelial state. Its knockdown elicited mesenchymal-to-epithelial transition on a molecular and functional level, and cells displayed decreased stemness and increased drug sensitivity. An analysis of human pancreatic cancer biopsies was concordant with these findings, because high levels of SUV420H2 correlated with a loss of epithelial characteristics in progressively invasive cancer. Together, these data indicate that SUV420H2 is an upstream epigenetic regulator of epithelial/mesenchymal state control.

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