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 ... -  《-》

Microfluidic co-culture of pancreatic tumor spheroids with stellate cells as a novel 3D model for investigation of stroma-mediated cell motility and drug resistance.

Lee JH ，Kim SK ，Khawar IA ，Jeong SY ，Chung S ，Kuh HJ ... -  《JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH》

Multiplex quantitative analysis of stroma-mediated cancer cell invasion, matrix remodeling, and drug response in a 3D co-culture model of pancreatic tumor spheroids and stellate cells.

Hwang HJ ，Oh MS ，Lee DW ，Kuh HJ ... -  《JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH》

Secretion of fibronectin by human pancreatic stellate cells promotes chemoresistance to gemcitabine in pancreatic cancer cells.

Amrutkar M ，Aasrum M ，Verbeke CS ，Gladhaug IP ... -  《BMC CANCER》

Biomaterial substrate-derived compact cellular spheroids mimicking the behavior of pancreatic cancer and microenvironment.

Pancreatic stromal cells especially pancreatic stellate cells (PSCs) play a critical role in the progression of human pancreatic ductal adenocarcinoma (PDAC). However, the exact interaction between cancer cells and PSCs remains to be elucidated in order to develop more effective therapeutic approaches to treat PDAC. The microenvironment of PDAC shows higher hyaluronan (HA) levels, which is associated with poor prognosis of PDAC patients. In the current study, an efficient three-dimensional tumor spheroid model for PDAC was established. The pancreatic cancer cells and PSCs were co-cultured on hyaluronan grafted chitosan (CS-HA) coated plates to generate 3D tumor-like co-spheroids. The pancreatic cancer cells and PSCs (1:9 ratio) co-cultured on CS-HA coated plates were assembled into tumor-like co-spheroids with 3D core-shell structure in 48 h. These spheroids displayed potent in vitro tumorigenicity such as up-regulated expression of stemness and migration markers. The migration rate of cancer cells in spheroids (from 1:9 cell ratio) was much faster (3.2-fold) than that of cancer cells alone. Meanwhile, this unique co-spheroidal cancer cell structure with the outer wrap of PSCs contributed to the chemo-resistance of pancreatic cancer cells to gemcitabine as well as sensitivity to the combined gemcitabine and Abraxane treatment in vitro. The metastatic nature of the spheroids was confirmed by the zebrafish xenograft model in vivo. The compact and dynamic pancreatic cancer-PSC co-spheroids generated by the unique 3D co-culture platform on CS-HA biomaterials can mimic the PSC-constituting microenvironment of PDAC and demonstrate the chemo-resistant, invasive, and metastatic phenotypes. They have potential applications in personalized and high-throughput drug screening.

Wong CW ，Han HW ，Tien YW ，Hsu SH ... -  《-》