Grainyhead-like 2 (GRHL2) regulates epithelial plasticity in pancreatic cancer progression.

The epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) contribute to cancer metastasis of pancreatic ductal adenocarcinoma (PDAC). We explored the role of grainyhead-like 2 (GRHL2), a suppressor of EMT, in the progression of PDAC. Expressions of GRHL2 were assessed using surgically resected PDAC tissues by immunohistochemistry analysis, and in vitro using human and mouse PDAC cells. Effects on epithelial plasticity and stemness of GRHL2 were examined in vitro using liver metastatic PDAC cells (CFPAC-1) with GRHL2 knockdown by specific siRNAs. GRHL2 has a significantly positive correlation with E-cadherin and CD133 in 155 resected human primary PDAC tissues. GRHL2 is highly expressed in liver metastatic cells than in primary invasive cells of both human and mouse PDAC, accompanied by a positive correlation with E-cadherin expression. GRHL2 knockdown CFPAC-1 cells demonstrated morphological changes into mesenchymal appearances and reduced proliferation through EMT. Notably, knockdown studies followed by flow cytometry analysis for a subpopulation of CD133+ showed that GRHL2 facilitates CFPAC-1 cells to maintain stem-like characters including self-renewal capacity and anoikis resistance. GRHL2 regulates epithelial plasticity along with stemness in PDAC, both of which are crucial for metastasis, implicating the possibility of GRHL2 as a therapeutic target for PDAC liver metastasis.

Nishino H ，Takano S ，Yoshitomi H ，Suzuki K ，Kagawa S ，Shimazaki R ，Shimizu H ，Furukawa K ，Miyazaki M ，Ohtsuka M ... -  《Cancer Medicine》

Metabolic programming of distinct cancer stem cells promotes metastasis of pancreatic ductal adenocarcinoma.

Nimmakayala RK ，Leon F ，Rachagani S ，Rauth S ，Nallasamy P ，Marimuthu S ，Shailendra GK ，Chhonker YS ，Chugh S ，Chirravuri R ，Gupta R ，Mallya K ，Prajapati DR ，Lele SM ，C Caffrey T ，L Grem J ，Grandgenett PM ，Hollingsworth MA ，Murry DJ ，Batra SK ，Ponnusamy MP ... -  《-》

GRHL2 inhibits colorectal cancer progression and metastasis via oppressing epithelial-mesenchymal transition.

Yang Z ，Wu D ，Chen Y ，Min Z ，Quan Y ... -  《-》

Expression of annexin II and stromal tenascin C promotes epithelial to mesenchymal transition and correlates with distant metastasis in pancreatic cancer.

Yoneura N ，Takano S ，Yoshitomi H ，Nakata Y ，Shimazaki R ，Kagawa S ，Furukawa K ，Takayashiki T ，Kuboki S ，Miyazaki M ，Ohtsuka M ... -  《-》

Cellular context-dependent interaction between cancer and stellate cells in hetero-type multicellular spheroids of pancreatic tumor.

Heterotypic cell-cell interaction between cancer cells and pancreatic stellate cells (PSCs) within tumor microenvironment is considered as a key mechanism for epithelial-mesenchymal transition (EMT) that triggers disease progression and chemoresistance in pancreatic ductal adenocarcinoma (PDAC). Hence, PSCs should be incorporated into in vitro co-culture models to maximize clinical relevance of data obtained using these models. In this study, we developed hetero-type spheroids of pancreatic cancer cells (ductal carcinoma cells PANC-1 and primacy sarcomatoid adenocarcinoma 36473 cells) and PSCs. Effect of PSC co-culture on the formation and growth of multicellular spheroids was cell-line dependent in that growth stimulation effect appeared in PANC-1/PSC spheroids, but not in 36473/PSC spheroids. Spatial distribution of PSCs within spheroids was also cell-line dependent. It was either confined to the center region (PANC-1) or evenly distributed (36473). Changes in expression levels of E-cadherin and vimentin revealed EMT induction in PANC-1/PSC hetero-type spheroids, but not in 36473/PSC spheroids. Gemcitabine sensitivity was increased partially by PSC co-culture. However, PSCs showed relative resistance to gemcitabine compared to PANC-1 cells in PANC-1/PSC spheroids. Overall, our hetero-type spheroid model can be used to study cancer-stroma interaction and their mechanism and evaluate anticancer drug activity. We demonstrated that stromal effect by PSC co-culture might be cellular context dependent with regard to growth stimulation and EMT induction. Hence, anti-stromal therapy should take these differences into consideration.

Nam S ，Khawar IA ，Park JK ，Chang S ，Kuh HJ ... -  《-》