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

Abstract

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.